Algorithm for optimized mRNA design improves stability and immunogenicity.

Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. 1-3), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products4. Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression5. Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, owing to synonymous codons, the mRNA design space is prohibitively large-for example, there are around 2.4 × 10632 candidate mRNA sequences for the SARS-CoV-2 spike protein. This poses insurmountable computational challenges. Here we provide a simple and unexpected solution using the classical concept of lattice parsing in computational linguistics, where finding the optimal mRNA sequence is analogous to identifying the most likely sentence among similar-sounding alternatives6. Our algorithm LinearDesign finds an optimal mRNA design for the spike protein in just 11 minutes, and can concurrently optimize stability and codon usage. LinearDesign substantially improves mRNA half-life and protein expression, and profoundly increases antibody titre by up to 128 times in mice compared to the codon-optimization benchmark on mRNA vaccines for COVID-19 and varicella-zoster virus. This result reveals the great potential of principled mRNA design and enables the exploration of previously unreachable but highly stable and efficient designs. Our work is a timely tool for vaccines and other mRNA-based medicines encoding therapeutic proteins such as monoclonal antibodies and anti-cancer drugs7,8.

Structural insight into selectivity of amylin and calcitonin receptor agonists.

Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a 'bypass' secondary structural motif (residues S19-P25). This study explored potential tuning of peptide selectivity through modification to residues 19-22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMY3R, and San45 bound to AMY3R or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMY3R. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.

Multi-regional sequencing reveals the genetic and immune heterogeneity of non-cancerous tissues in gastric cancer.

Gastric cancer (GC) is one of the most heterogeneous tumors. However, research on normal tissue adjacent to the tumor (NAT) is very limited. We performed multi-regional omics sequencing on 150 samples to assess the genetic basis and immune microenvironment in NAT and matched primary tumor or lymph node metastases. NATs demonstrated different mutated genes compared with GC, and NAT genomes underwent independent evolution with low variant allele frequency. Mutation profiles were predominated by aging and smoking-associated signatures in NAT instead of signatures associated with genetic instability. Although the immune microenvironment within NATs shows substantial intra-patient heterogeneity, the proportion of shared TCR clones among NATs is five times higher than that of tumor regions. These findings support the notion that subclonal expansion is not pronounced in NATs. We also demonstrated remarkable intra-patient heterogeneity of GCs and revealed heterogeneity of focal amplification of CD274 (encoding PD-L1) that leads to differential expression. Finally, we identified that monoclonal seeding is predominant in GC, which is followed by metastasis-to-metastasis dissemination in individual lymph nodes. These results provide novel insights into GC carcinogenesis. © 2024 The Pathological Society of Great Britain and Ireland.

Machine Learning for Experimental Reactivity of a Set of Metal Clusters toward C-H Activation.

Understanding the mechanisms of C-H activation of alkanes is a very important research topic. The reactions of metal clusters with alkanes have been extensively studied to reveal the electronic features governing C-H activation, while the experimental cluster reactivity was qualitatively interpreted case by case in the literature. Herein, we prepared and mass-selected over 100 rhodium-based clusters (RhxVyOz- and RhxCoyOz-) to react with light alkanes, enabling the determination of reaction rate constants spanning six orders of magnitude. A satisfactory model being able to quantitatively describe the rate data in terms of multiple cluster electronic features (average electron occupancy of valence s orbitals, the minimum natural charge on the metal atom, cluster polarizability, and energy gap involved in the agostic interaction) has been constructed through a machine learning approach. This study demonstrates that the general mechanisms governing the very important process of C-H activation by diverse metal centers can be discovered by interpreting experimental data with artificial intelligence.

Huogu injection protects against SONFH by promoting osteogenic differentiation of BMSCs and preventing osteoblast apoptosis.

To investigate the effect and mechanism of Huogu injection (HG) on steroid-induced osteonecrosis of the femoral head (SONFH), we established a SONFH model in rabbits using horse serum and dexamethasone (DEX) and applied HG locally at the hip joint. We evaluated the therapeutic efficacy at 4 weeks using scanning electron microscopy (SEM), micro-CT, and qualitative histology including H&E, Masson's trichrome, ALP, and TUNEL staining. In vitro, we induced osteogenic differentiation of bone marrow stromal cells (BMSCs) and performed analysis on days 14 and 21 of cell differentiation. The findings, in vivo, including SEM, micro-CT, and H&E staining, showed that HG significantly maintained bone quality and trabecular number. ALP staining indicated that HG promoted the proliferation of bone cells. Moreover, the results of Masson's trichrome staining demonstrated the essential role of HG in collagen synthesis. Additionally, TUNEL staining revealed that HG reduced apoptosis. ALP and ARS staining in vitro confirmed that HG enhanced osteogenic differentiation and mineralization, consistent with the WB and qRT-PCR analysis. Furthermore, Annexin V-FITC/PI staining verified that HG inhibited osteoblast apoptosis, in agreement with the WB and qRT-PCR analyses. Furthermore, combined with the UPLC analysis, we found that naringin enhanced the osteogenic differentiation and accelerated the deposition of calcium phosphate. Salvianolic acid B protected osteoblasts derived from BMSCs against GCs-mediated apoptosis. Thus, this study not only reveals the mechanism of HG in promoting osteogenesis and anti-apoptosis of osteoblasts but also identifies the active-related components in HG, by which we provide the evidence for the application of HG in SONFH.

Pre- and Post-treatment Double-Sequential-Point Dynamic Radiomic Model in the Response Prediction of Gastric Cancer to Neoadjuvant Chemotherapy: 3-Year Survival Analysis.

BACKGROUND: Prognosis prediction of patients with gastric cancer after neoadjuvant chemotherapy is suboptimal. This study aims to develop and validate a dynamic radiomic model for prognosis prediction of patients with gastric cancer on the basis of baseline and posttreatment features. PATIENTS AND METHODS: This single-center cohort study included patients with gastric adenocarcinoma treated with neoadjuvant chemotherapy from June 2009 to July 2015 in the Gastrointestinal Cancer Center of Peking University Cancer Hospital. Their clinicopathological data, pre-treatment and post-treatment computed tomography (CT) images, and pathological reports were retrieved and analyzed. Four prediction models were developed and validated using tenfold cross-validation, with death within 3 years as the outcome. Model discrimination was compared by the area under the curve (AUC). The final radiomic model was evaluated for calibration and clinical utility using Hosmer-Lemeshow tests and decision curve analysis. RESULTS: The study included 205 patients with gastric adenocarcinoma [166 (81%) male; mean age 59.9 (SD 10.3) years], with 71 (34.6%) deaths occurring within 3 years. The radiomic model alone demonstrated better discrimination than the pathological T stage (ypT) stage model alone (cross-validated AUC 0.598 versus 0.516, P = 0.009). The final radiomic model, which incorporated both radiomic and clinicopathological characteristics, had a significantly higher cross-validated AUC (0.769) than the ypT stage model (0.516), the radiomics alone model (0.598), and the ypT plus other clinicopathological characteristics model (0.738; all P < 0.05). Decision curve analysis confirmed the clinical utility of the final radiomic model. CONCLUSIONS: The developed radiomic model had good accuracy and could be used as a decision aid tool in clinical practice to differentiate prognosis of patients with gastric cancer.

Short-term outcomes and long-term quality of life of reconstruction methods after proximal gastrectomy: a systematic review and meta-analysis.

BACKGROUND: The optimal reconstruction method after proximal gastrectomy remains unclear. This systematic review and meta-analysis aimed to compare the short-term outcomes and long-term quality of life of various reconstruction methods. METHODS: PubMed, Embase, Web of Science and Cochrane Library were searched to identify comparative studies concerning the reconstruction methods after proximal gastrectomy. The reconstruction methods were classified into six groups: double tract reconstruction (DTR), esophagogastrostomy (EG), gastric tube reconstruction (GT), jejunal interposition (JI), jejunal pouch interposition (JPI) and double flap technique (DFT). Esophagogastric anastomosis group (EG group) included EG, GT and DFT, while esophagojejunal anastomosis group (EJ group) included DTR, JI and JPI. RESULTS: A total of 27 studies with 2410 patients were included in this meta-analysis. The pooled results indicated that the incidences of reflux esophagitis of DTR, EG, GT, JI, JPI and DFT were 7.6%, 27.3%, 4.5%, 7.1%, 14.0%, and 9.1%, respectively. The EG group had more reflux esophagitis (OR = 3.68, 95%CI 2.44-5.57, P < 0.00001) and anastomotic stricture (OR = 1.58, 95%CI 1.02-2.45, P = 0.04) than the EJ group. But the EG group showed shorter operation time (MD=-56.34, 95%CI -76.75- -35.94, P < 0.00001), lesser intraoperative blood loss (MD=-126.52, 95%CI -187.91- -65.12, P < 0.0001) and shorter postoperative hospital stay (MD=-2.07, 95%CI -3.66- -0.48, P = 0.01). Meanwhile, the EG group had fewer postoperative complications (OR = 0.68, 95%CI 0.51-0.90, P = 0.006) and lesser weight loss (MD=-1.25, 95%CI -2.11- -0.39, P = 0.004). For specific reconstruction methods, there were lesser reflux esophagitis (OR = 0.10, 95%CI 0.06-0.18, P < 0.00001) and anastomotic stricture (OR = 0.14, 95%CI 0.06-0.33, P < 0.00001) in DTR than the esophagogastrostomy. DTR and esophagogastrostomy showed no significant difference in anastomotic leakage (OR = 1.01, 95%CI 0.34-3.01, P = 0.98). CONCLUSION: Esophagojejunal anastomosis after proximal gastrectomy can reduce the incidences of reflux esophagitis and anastomotic stricture, while esophagogastric anastomosis has advantages in technical simplicity and long-term weight status. Double tract reconstruction is a safe technique with excellent anti-reflux effectiveness and favorable quality of life. REGISTRATION: This meta-analysis was registered on the PROSPERO (CRD42022381357).

Spectroscopic Characterization of Thermal Methane Activation by Lewis-Acid-Base Pair in a Gas-Phase Metal Nitride Anion Ta2N3.

Activation and transformation of methane is one of the "holy grails" in catalysis. Understanding the nature of active sites and mechanistic details via spectroscopic characterization of the reactive sites and key intermediates is of great challenge but crucial for the development of novel strategies for methane transformation. Herein, by employing photoelectron velocity-map imaging (PEVMI) spectroscopy in conjunction with quantum chemistry calculations, the Lewis acid-base pair (LABP) of [Taδ+-Nδ-] unit in Ta2N3 - acting as an active center to accomplish the heterolytic cleavage of C-H bond in CH4 has been confirmed by direct characterization of the reactant ion Ta2N3 - and the CH4-adduct intermediate Ta2N3CH4 -. Two active vibrational modes for the reactant (Ta2N3 -) and four active vibrational modes for the intermediate (Ta2N3CH4 -) were observed from the vibrationally resolved PEVMI spectra, which unequivocally determined the structure of Ta2N3 - and Ta2N3CH4 -. Upon heating, the LABP intermediate (Ta2N3CH4 -) containing the NH and Ta-CH3 unit can undergo the processes of C-N coupling and dehydrogenation to form the product with an adsorbed HCN molecule.

Toward Designing Reactive Metal Clusters for Dinitrogen Activation: A Guideline Based on N2 Initial Adsorption.

Gas-phase metal clusters are ideal models to explore transition-metal-mediated N2 activation mechanism. However, the effective design and search of reactive clusters in N2 activation are currently hindered by the lack of clear guidelines. Inspired by the Sabatier principle, we discovered in this work that N2 initial adsorption energy (ΔEads) is an important parameter to control the N2 activation reactivity of metal clusters in the gas phase. This mechanistic insight obtained from high-level calculations rationalizes the N2 activation reactivity of many previously reported metal clusters when combined with the known factor determining the N≡N cleavage process. Furthermore, based on this guideline of ΔEads, we successfully designed several new reactive clusters for cleaving N≡N triple bond under mild conditions, including FeV2S2-, TaV2C2-, and TaV2C3-, the high N2 activation reactivity of which has been fully corroborated in our gas phase experiments employing mass spectrometry with collision-induced dissociation. The importance of ΔEads revealed in this work not only reshapes our understanding of N2 activation reactions in the gas phase but also could have implication for other N2 activation processes in the condensed phase. The more general establishment of this new perspective on N2 activation reactivity warrants future experimental and computational studies.

Safety and short-term outcomes of a modified valvuloplastic esophagogastrostomy versus gastric tube anastomosis after laparoscopy-assisted proximal gastrectomy: a retrospective cohort study.

BACKGROUND: There is no optimal reconstruction method after proximal gastrectomy. The valvuloplastic esophagogastrostomy can reduce postoperative reflux esophagitis, but it is technically complex with a long operation time. The gastric tube anastomosis is technically simple, but the incidences of reflux esophagitis and anastomotic stricture are higher. METHODS: We have devised a modified valvuloplastic esophagogastrostomy after laparoscopy-assisted proximal gastrectomy (LAPG), the arch-bridge anastomosis. After reviewing our prospectively maintained gastric cancer database, 43 patients who underwent LAPG from November 2021 to April 2023 were included in this cohort study, with 25 patients received the arch-bridge anastomosis and 18 patients received gastric tube anastomosis. The short-term outcomes were compared between the two groups to evaluate the efficacy of the arch-bridge anastomosis. Reporting was consistent with the STROCSS 2021 guideline. RESULTS: The median operation time was 180 min in the arch-bridge group, significantly shorter than the gastric tube group (p = 0.003). In the arch-bridge group, none of the 25 patients experienced anastomotic leakage, while one patient (4%) experienced anastomotic stricture requiring endoscopic balloon dilation. The postoperative length of stay was shorter in the arch-bridge group (9 vs. 11, p = 0.034). None of the patients in the arch-bridge group experienced gastroesophageal reflux and used proton pump inhibitor (PPI), while four (22.2%) patients in the gastric tube group used PPI (p = 0.025). The incidence of reflux esophagitis (Los Angeles grade B or more severe) by endoscopy was lower in the arch-bridge group (0% vs. 25.0%). CONCLUSION: The arch-bridge anastomosis is a safe, time-saving, and feasible reconstruction method. It can reduce postoperative reflux and anastomotic stricture incidences in a selected cohort of patients undergoing laparoscopy-assisted proximal gastrectomy.

A novel reverse perilesional home phototherapy can promote the repigmentation of vitiligo patches with complete leukotrichia: A 12-week, open-label, double-arm, multicenter, randomized clinical trial.

BACKGROUND/PURPOSE: Existing phototherapies are ineffective for treating patients with vitiligo with complete leukotrichia. We compared the efficacy of reverse perilesional irradiation, during which only the lesional areas are covered, with conventional narrowband ultraviolet B (NB-UVB) home phototherapy for repigmentation of non-segmental vitiligo in patients with complete leukotrichia. METHODS: This was a 12-week, open-label, double-arm, multicenter clinical trial, with a total of 121 patients with non-segmental vitiligo who were randomly divided into two groups (both received topical tacrolimus): the conventional NB-UVB irradiation (CI) and reverse perilesional NB-UVB irradiation (RI) groups. RESULTS: A statistically significant difference in improvement from baseline was observed in the RI group compared with the findings in the CI group (-30.8% ± 11.8% vs. -25.5% ± 11.05%, respectively [p = .010]; pair-wise comparison p = .900 at week 4, p = .104 at week 8, and p = .010 at week 12). At week 12, the average percentage change from baseline of leukotrichia in the irradiation area significantly decreased from 100% to 82.2% ± 13.65% in the RI group, and from 100% to 88.7% ± 9.64% in the CI group (p = .027). Adverse events were minor, including desquamation, dryness, erythema, and blisters. No severe or lasting side effects were observed during the study. CONCLUSION: RI mediated better repigmentation of vitiligo with complete leukotrichia than CI.

Artificial intelligence for neuro MRI acquisition: a review.

OBJECT: To review recent advances of artificial intelligence (AI) in enhancing the efficiency and throughput of the MRI acquisition workflow in neuroimaging, including planning, sequence design, and correction of acquisition artifacts. MATERIALS AND METHODS: A comprehensive analysis was conducted on recent AI-based methods in neuro MRI acquisition. The study focused on key technological advances, their impact on clinical practice, and potential risks associated with these methods. RESULTS: The findings indicate that AI-based algorithms have a substantial positive impact on the MRI acquisition process, improving both efficiency and throughput. Specific algorithms were identified as particularly effective in optimizing acquisition steps, with reported improvements in workflow efficiency. DISCUSSION: The review highlights the transformative potential of AI in neuro MRI acquisition, emphasizing the technological advances and clinical benefits. However, it also discusses potential risks and challenges, suggesting areas for future research to mitigate these concerns and further enhance AI integration in MRI acquisition.

Magnetic covalent organic frameworks for extraction and determination of endocrine-disrupting chemicals in beverage and water samples.

BACKGROUND: Phenolic endocrine-disrupting chemicals (EDCs) are widespread and easily ingested through the food chain. They pose a serious threat to human health. Magnetic solid-phase extraction (MSPE) is an effective sample pre-treatment technology to determine traces of phenolic EDCs. RESULTS: Magnetic covalent organic framework (COF) (Fe3 O4 @COF) nanospheres were prepared and characterized. The efficient and selective extraction of phenolic EDCs relies on a large specific surface and the inherent porosity of COFs and hydrogen bonding, π-π, and hydrophobic interactions between COF shells and phenolic EDCs. Under optimal conditions, the proposed magnetic solid-phase extraction-high-performance liquid chromatography-ultra violet (MSPE-HPLC-UV) based on the metallic covalent organic framework method for phenolic EDCs shows good linearities (0.002-6 µg mL-1 ), with R2 of 0.995 or higher, and low limits of detection (6-1.200 ng mL-1 ). CONCLUSION: Magnetic covalent organic frameworks (Fe3 O4 @COFs) with good MSPE performance for phenolic EDCs were synthesized by the solvothermal method. The magnetic covalent organic framework-based MSPE-HPLC-UV method was applied successfully to determine phenolic EDCs in beverage and water samples with satisfactory recoveries (90.200%-123%) and relative standard deviations (2.100%-12.100%). © 2023 Society of Chemical Industry.

Genomic characterization of peritoneal lavage cytology-positive gastric cancer.

Objective: Positive peritoneal lavege cytology (CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1 and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer. Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31 matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer. Results: Least absolute shrinkage and selection operator (LASSO) algorithm identified 43 cytology-positive marker genes, while MutSigCV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology (CY0). Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1 and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Selective Reduction of NO into N2 Catalyzed by Rh1-Doped Cluster Anions RhCe2O3-5.

Catalytic conversion of toxic nitrogen oxide (NO) and carbon monoxide (CO) into nitrogen (N2) and carbon dioxide (CO2) is imperative under the weight of the increasingly stringent emission regulations, while a fundamental understanding of the nature of the active site to selectively drive N2 generation is elusive. Herein, in combination with state-of-the-art mass-spectrometric experiments and quantum-chemical calculations, we demonstrated that the rhodium-cerium oxide clusters RhCe2O3-5- can catalytically drive NO reduction by CO and give rise to N2 and CO2. This finding represents a sharp improvement in cluster science where N2O is commonly produced in the rarely established examples of catalytic NO reduction mediated with gas-phase clusters. We demonstrated the importance of the unique chemical environment in the RhCe2O3- cluster to guide the substantially improved N2 selectivity: a triatomic Lewis "acid-base-acid" Ceδ+-Rhδ--Ceδ+ site is proposed to strongly adsorb two NO molecules as well as the N2O intermediate that is attached on the Rh atom and can facilely dissociate to form N2 assisted by both Ce atoms.

Sampling strategies and integrated reconstruction for reducing distortion and boundary slice aliasing in high-resolution 3D diffusion MRI.

PURPOSE: To develop a new method for high-fidelity, high-resolution 3D multi-slab diffusion MRI with minimal distortion and boundary slice aliasing. METHODS: Our method modifies 3D multi-slab imaging to integrate blip-reversed acquisitions for distortion correction and oversampling in the slice direction (kz ) for reducing boundary slice aliasing. Our aim is to achieve robust acceleration to keep the scan time the same as conventional 3D multi-slab acquisitions, in which data are acquired with a single direction of blip traversal and without kz -oversampling. We employ a two-stage reconstruction. In the first stage, the blip-up/down images are respectively reconstructed and analyzed to produce a field map for each diffusion direction. In the second stage, the blip-reversed data and the field map are incorporated into a joint reconstruction to produce images that are corrected for distortion and boundary slice aliasing. RESULTS: We conducted experiments at 7T in six healthy subjects. Stage 1 reconstruction produces images from highly under-sampled data (R = 7.2) with sufficient quality to provide accurate field map estimation. Stage 2 joint reconstruction substantially reduces distortion artifacts with comparable quality to fully-sampled blip-reversed results (2.4× scan time). Whole-brain in-vivo results acquired at 1.22 mm and 1.05 mm isotropic resolutions demonstrate improved anatomical fidelity compared to conventional 3D multi-slab imaging. Data demonstrate good reliability and reproducibility of the proposed method over multiple subjects. CONCLUSION: The proposed acquisition and reconstruction framework provide major reductions in distortion and boundary slice aliasing for 3D multi-slab diffusion MRI without increasing the scan time, which can potentially produce high-quality, high-resolution diffusion MRI.

Dinitrogen Activation in the Gas Phase: Spectroscopic Characterization of C-N Coupling in the V3 C+ +N2 Reaction.

We report on cluster-mediated C-N bond formation in the gas phase using N2 as a nitrogen source. The V3 C+ +N2 reaction is studied by a combination of ion-trap mass spectrometry with infrared photodissociation (IRPD) spectroscopy and complemented by electronic structure calculations. The proposed reaction mechanism is spectroscopically validated by identifying the structures of the reactant and product ions. V3 C+ exhibits a pyramidal structure of C1 -symmetry. N2 activation is initiated by adsorption in an end-on fashion at a vanadium site, followed by spontaneous cleavage of the N≡N triple bond and subsequent C-N coupling. The IRPD spectrum of the metal nitride product [NV3 (C=N)]+ exhibits characteristic C=N double bond (1530 cm-1 ) and V-N single bond (770, 541 and 522 cm-1 ) stretching bands.

Myelin Debris Impairs Tight Junctions and Promotes the Migration of Microvascular Endothelial Cells in the Injured Spinal Cord.

Clearance of myelin debris caused by acute demyelination is an essential process for functional restoration following spinal cord injury (SCI). Microvascular endothelial cells, acting as "amateur" phagocytes, have been confirmed to engulf and degrade myelin debris, promoting the inflammatory response, robust angiogenesis, and persistent fibrosis. However, the effect of myelin debris engulfment on the function of endothelial tight junctions (TJs) remains unclear. Here, we demonstrate that myelin debris uptake impairs TJs and gap junctions of endothelial cells in the lesion core of the injured spinal cord and in vitro, resulting in increased permeability and leakage. We further show that myelin debris acts as an inducer to regulate the endothelial-to-mesenchymal transition in a dose-dependent manner and promotes endothelial cell migration through the PI3K/AKT and ERK signaling pathways. Together, our results indicate that myelin debris engulfment impairs TJs and promotes the migration of endothelial cells. Accelerating myelin debris clearance may help maintain blood-spinal cord barrier integrity, thus facilitating restoration of motor and sensory function following SCI.

Superior Reactivity of Molybdenum-Sulfur Cluster Anions Mo5S2- and Mo5S3- toward Dinitrogen.

Inspired by the fact that Mo is a key element in biological nitrogenase, a series of gas-phase MoxSy- cluster anions are prepared and their reactivity toward N2 is investigated by the combination of mass spectrometry, photoelectron imaging spectroscopy, and density functional theory calculations. The Mo5S2- and Mo5S3- cluster anions show remarkable reactivity compared with the anionic species reported previously. The spectroscopic results in conjunction with theoretical analysis reveal that a facile cleavage of N≡N bonds takes place on Mo5S2- and Mo5S3-. The large dissociative adsorption energy of N2 and the favorable entrance channel for initial N2 approaching are proposed as two decisive factors for the superior reactivity of Mo5S2- and Mo5S3-. Besides, the modulation of S ligands on the reactivity of metal centers with N2 is proposed. The highly reactive metal-sulfur species may be obtained by the coordination of two to three sulfur atoms to bare metal clusters so that an appropriate combination of electronic structures and charge distributions can be achieved.