Insights into the Mechanism of Metal-Catalyzed Transformation of Oxime Esters: Metal-Bound Radical Pathway vs Free Radical Pathway

Controlling of radical reactivity by binding a radical to the metal center is an elegant strategy to overcome the challenge that radical intermediates are “too reactive to be selective”. Yet, its application has seemingly been limited to a few strained-ring substrates, azide compounds, and diazo compounds. Meanwhile, first-row transition-metal-catalyzed (mainly, Fe, Ni, Cu) transformations of oxime esters have been reported recently in which the activation processes are assumed to follow free-radical mechanisms. In this work, we show by means of density functional theory calculations that the activation of oxime esters catalyzed by Fe­(II) and Cu­(I) catalysts more likely affords a metal-bound iminyl radical, rather than the presumed free iminyl radical, and the whole process follows a metal-bound radical mechanism. The as-formed metal-bound radical intermediates are an Fe­(III)-iminyl radical (Stotal = 2, SFe = 5/2, and Siminyl = −1/2) and a Cu­(II)-iminyl radical (Stotal = 0, SCu = 1/2, and Siminyl = −1/2). The discovery of such novel substrates affording metal-bound radical intermediates may facilitate the experimental design of metal-catalyzed asymmetric synthesis using oxime esters to achieve the desired enantioselectivity

Datasheet1_Predicting pneumonia during hospitalization in flail chest patients using machine learning approaches.docx

ObjectivePneumonia is a common pulmonary complication of flail chest, causing high morbidity and mortality rates in affected patients. The existing methods for identifying pneumonia have low accuracy, and their use may delay antimicrobial therapy. However, machine learning can be combined with electronic medical record systems to identify information and assist in quick clinical decision-making. Our study aimed to develop a novel machine-learning model to predict pneumonia risk in flail chest patients.MethodsFrom January 2011 to December 2021, the electronic medical records of 169 adult patients with flail chest at a tertiary teaching hospital in an urban level I Trauma Centre in Chongqing were retrospectively analysed. Then, the patients were randomly divided into training and test sets at a ratio of 7:3. Using the Fisher score, the best subset of variables was chosen. The performance of the seven models was evaluated by computing the area under the receiver operating characteristic curve (AUC). The output of the XGBoost model was shown using the Shapley Additive exPlanation (SHAP) method.ResultsOf 802 multiple rib fracture patients, 169 flail chest patients were eventually included, and 86 (50.80%) were diagnosed with pneumonia. The XGBoost model performed the best among all seven machine-learning models. The AUC of the XGBoost model was 0.895 (sensitivity: 84.3%; specificity: 80.0%).Pneumonia in flail chest patients was associated with several features: systolic blood pressure, pH value, blood transfusion, and ISS.ConclusionOur study demonstrated that the XGBoost model with 32 variables had high reliability in assessing risk indicators of pneumonia in flail chest patients. The SHAP method can identify vital pneumonia risk factors, making the XGBoost model's output clinically meaningful.</p

DataSheet_1_Complete Protection Against Yersinia pestis in BALB/c Mouse Model Elicited by Immunization With Inhalable Formulations of rF1-V10 Fusion Protein via Aerosolized Intratracheal Inoculation.pdf

Pneumonic plague, caused by Yersinia pestis, is an infectious disease with high mortality rates unless treated early with antibiotics. Currently, no FDA-approved vaccine against plague is available for human use. The capsular antigen F1, the low-calcium-response V antigen (LcrV), and the recombinant fusion protein (rF1-LcrV) of Y. pestis are leading subunit vaccine candidates under intense investigation; however, the inability of recombinant antigens to provide complete protection against pneumonic plague in animal models remains a significant concern. In this study, we compared immunoprotection against pneumonic plague provided by rF1, rV10 (a truncation of LcrV), and rF1-V10, and vaccinations delivered via aerosolized intratracheal (i.t.) inoculation or subcutaneous (s.c.) injection. We further considered three vaccine formulations: conventional liquid, dry powder produced by spray freeze drying, or dry powder reconstituted in PBS. The main findings are: (i) rF1-V10 immunization with any formulation via i.t. or s.c. routes conferred 100% protection against Y. pestis i.t. infection; (ii) rF1 or rV10 immunization using i.t. delivery provided significantly stronger protection than rF1 or rV10 immunization via s.c. delivery; and (iii) powder formulations of subunit vaccines induced immune responses and provided protection equivalent to those elicited by unprocessed liquid formulations of vaccines. Our data indicate that immunization with a powder formulation of rF1-V10 vaccines via an i.t. route may be a promising vaccination strategy for providing protective immunity against pneumonic plague.</p

DataSheet_1_Aerosolized Intratracheal Inoculation of Recombinant Protective Antigen (rPA) Vaccine Provides Protection Against Inhalational Anthrax in B10.D2-Hc0 Mice.pdf

Anthrax caused by Bacillus anthracis is a fatal zoonotic disease with a high lethality and poor prognosis. Inhalational anthrax is the most severe of the three forms of anthrax. The currently licensed commercial human anthrax vaccines require a complex immunization procedure for efficacy and have side effects that limit its use in emergent situations. Thus, development of a better anthrax vaccine is necessary. In this study, we evaluate the potency and efficacy of aerosolized intratracheal (i.t.) inoculation with recombinant protective antigen (rPA) subunit vaccines against aerosolized B. anthracis Pasteur II spores (an attenuated strain) challenge in a B10.D2-Hc0 mouse (deficient in complement component C5) model. Immunization of rPA in liquid, powder or powder reconstituted formulations via i.t. route conferred 100% protection against a 20× LD50 aerosolized Pasteur II spore challenge in mice, compared with only 50% of subcutaneous (s.c.) injection with liquid rPA. Consistently, i.t. inoculation of rPA vaccines induced a higher lethal toxin (LeTx) neutralizing antibody titer, a stronger lung mucosal immune response and a greater cellular immune response than s.c. injection. Our results demonstrate that immunization with rPA dry powder vaccine via i.t. route may provide a stable and effective strategy to improve currently available anthrax vaccines and B10.D2-Hc0 mice challenged with B. anthracis attenuated strains might be an alternative model for anthrax vaccine candidate screening.</p