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Cyclopropanes represent a class of versatile building blocks in modern organic synthesis. While the release of ring strain offers a thermodynamic driving force, the control of selectivity for C–C bond cleavage and the subsequent regiochemistry of the functionalization remains difficult, especially for unactivated cyclopropanes. Here we report a photoredox-coupled ring-opening oxo-amination of electronically unbiased cyclopropanes, which enables the expedient construction of a host of structurally diverse β -amino ketone derivatives. Through one electron oxidation, the relatively inert aryl cyclopropanes are readily converted into reactive radical cation intermediates, which in turn participate in the ensuing ring-opening functionalizations. Based on mechanistic studies, the present oxo-amination is proposed to proceed through an S N 2-like nucleophilic attack/ring-opening manifold. This protocol features wide substrate scope, mild reaction conditions, and use of dioxygen as an oxidant both for catalyst regeneration and oxygen-incorporation. Moreover, a one-pot formal aminoacylation of olefins is described through a sequential cyclopropanation/oxo-amination. The ring-opening and functionalization of electronically unbiased cyclopropanes is highly challenging to achieve in a regioselective fashion. Here, the authors report a mild photoredox-coupled oxoamination of electronically unactivated aryl cyclopropanes with simple azaarenes and molecular oxygen.

Background COVID-19 is highly contagious, and the crude mortality rate could reach 49% in critical patients. Inflammation concerns on disease progression. This study analyzed blood inflammation indicators among mild, severe and critical patients, helping to identify severe or critical patients early. Methods In this cross-sectional study, 100 patients were included and divided into mild, severe or critical groups according to disease condition. Correlation of peripheral blood inflammation-related indicators with disease criticality was analyzed. Cut-off values for critically ill patients were speculated through the ROC curve. Results Significantly, disease severity was associated with age ( R  = -0.564, P  < 0.001), interleukin-2 receptor (IL2R) ( R  = -0.534, P  < 0.001), interleukin-6 (IL-6) ( R  = -0.535, P  < 0.001), interleukin-8 (IL-8) ( R  = -0.308, P  < 0.001), interleukin-10 (IL-10) ( R  = -0.422, P  < 0.001), tumor necrosis factor α (TNFα) ( R  = -0.322, P  < 0.001), C-reactive protein (CRP) ( R  = -0.604, P  < 0.001), ferroprotein ( R  = -0.508, P  < 0.001), procalcitonin ( R  = -0.650, P  < 0.001), white cell counts (WBC) ( R  = -0.54, P  < 0.001), lymphocyte counts (LC) ( R  = 0.56, P  < 0.001), neutrophil count (NC) ( R  = -0.585, P  < 0.001) and eosinophil counts (EC) ( R  = 0.299, P  < 0.001). With IL2R > 793.5 U/mL or CRP > 30.7 ng/mL, the progress of COVID-19 to critical stage should be closely observed and possibly prevented. Conclusions Inflammation is closely related to severity of COVID-19, and IL-6 and TNFα might be promising therapeutic targets.

Metal single-atom catalysts (M-SACs) have emerged as an attractive concept for promoting heterogeneous reactions, but the synthesis of high-loading M-SACs remains a challenge. Here, we report a multilayer stabilization strategy for constructing M-SACs in nitrogen-, sulfur- and fluorine-co-doped graphitized carbons (M = Fe, Co, Ru, Ir and Pt). Metal precursors are embedded into perfluorotetradecanoic acid multilayers and are further coated with polypyrrole prior to pyrolysis. Aggregation of the metals is thus efficiently inhibited to achieve M-SACs with a high metal loading (~16 wt%). Fe-SAC serves as an efficient oxygen reduction catalyst with half-wave potentials of 0.91 and 0.82 V (versus reversible hydrogen electrode) in alkaline and acid solutions, respectively. Moreover, as an air electrode in zinc–air batteries, Fe-SAC demonstrates a large peak power density of 247.7 mW cm −2 and superior long-term stability . Our versatile method paves an effective way to develop high-loading M-SACs for various applications. Metal single-atom catalysts offer great potential in bridging the gap between heterogeneous and homogeneous catalysis. Here the authors demonstrate a multilayer stabilization strategy for fabricating high-loading single-atom catalysts including non-precious and noble metals.

The integrated heterogeneous 7G/8G networks may face multiple challenges for reliable data delivery such as link disruption, intermittent link availability, long latency and a highly lossy channel. Delay tolerant networking (DTN) was proposed as a highly reliable networking technology for space networks that will be part of future 7G/8G networks. In this paper, an experimental evaluation of transmission control protocol (TCP)-based DTN (i.e., running TCP at the transport layer of DTN) for space-vehicle communications in the cislunar domain is presented. The impact of link disruption is also considered. The evaluation was conducted using the DTN protocol suites over a realistic experimental testbed. The study results show that TCP-based DTN works effectively for space-vehicle communications in cislunar domain in the presence of a link disruption event. However, a roughly exponential goodput decrease is observed with a linear increase in link delay from 1250 ms to 5 s.

Gastrointestinal cancer is a leading cause of cancer-related mortality and remains a major challenge for cancer treatment. Despite the combined administration of modern surgical techniques and chemoradiotherapy (CRT), the overall 5-year survival rate of gastrointestinal cancer patients in advanced stage disease is less than 15%, due to rapid disease progression, metastasis, and CRT resistance. A better understanding of the mechanisms underlying cancer progression and optimized treatment strategies for gastrointestinal cancer are urgently needed. With increasing evidence highlighting the protective role of immune responses in cancer initiation and progression, immunotherapy has become a hot research topic in the integrative management of gastrointestinal cancer. Here, an overview of the molecular understanding of colorectal cancer, esophageal cancer and gastric cancer is provided. Subsequently, recently developed immunotherapy strategies, including immune checkpoint inhibitors, chimeric antigen receptor T cell therapies, tumor vaccines and therapies targeting other immune cells, have been described. Finally, the underlying mechanisms, fundamental research and clinical trials of each agent are discussed. Overall, this review summarizes recent advances and future directions for immunotherapy for patients with gastrointestinal malignancies.

PurposeIt is widely acknowledged that the mechanical behavior of a soil is significantly influenced by the soil microstructure; and the microstructure can evolve as a result of any mechanical, hydraulic, chemical or thermal change taken place on soil sample. The present study aimed to investigate the microstructures of intact loess and remolded loess and to explore the evolution of the microstructure and PSD (pore-size distribution) due to consolidation for both intact and remolded loess.Materials and methodsA loess from the Loess Plateau of China was used as test material. A series of intact loess specimens were consolidated to various vertical pressures in oedometer cells. The same loess was remolded at the optimum water content state to various compaction degrees using static compaction method. It is equivalent to consolidate the remolded loess with the least compaction degree under various stress levels. The microstructures of intact loess specimens after consolidation tests and remolded loess specimens are characterized using the SEM (scanning electron microscope) and MIP (mercury intrusion porosimetry) techniques. The micrographs and PSDs under various consolidation pressures (or compaction energies) were compared to investigate the evolution of the microstructure and PSD induced by mechanical loading for each kind of soil.Results and discussionThe microstructure of intact loess is more homogeneous and is less dependent on consolidation stress than remolded loess. In both soils, the pores with entrance diameter smaller than 6 μm are almost not influenced by consolidation. In intact loess, inter-aggregate pores with entrance diameter greater than 6 μm are compressed randomly due to loading. However, in remolded loess, the pores are compressed until all larger pores have been compressed. The cumulative pore volume curve of remolded loess of any compaction degree can be divided into two segments, large-pore segment (6–50 μm) and small-pore segment (< 6 μm). The large-pore segment is simplified into a horizontal line and a straight line which slope is independent on the compactness.ConclusionsRemolded loess has very different microstructure and PSD from intact loess even though they may have the same GSD (grain-size distribution), mineralogical composition, and some other physical properties. The microstructural evolution induced by mechanical loading also varies in both kinds of soils. Based upon the measured PSDs, a method is proposed for predicting the PSD of remolded loess of any compaction degree using a reference PSD.

It is well known that the hydromechanical behavior of both saturated and unsaturated loess soils is significantly influenced by the soil fabric. However, there is limited understanding of how the soil fabric or structure evolves due to mechanical, hydraulic and chemical changes on loess soils. Information of the microstructural evolution or change in pore-size distribution (i.e., PSD) of loess soils along different stress paths is valuable for proposing an advanced constitutive model that considers the microstructure and can better model the hydromechanical behavior of loess soils. For this reason, in the present study, the microstructure is characterized on intact and saturated loess specimens before and after oedometer consolidation tests, using scanning electron microscopy and mercury intrusion porosimetry methods. The results suggest that the loading-induced change in PSD varies with stress level and saturation state of the loess soil. A reduction arises in the cumulative intrusion void ratio due to an increase in vertical stress, which accounts for compression of inter-aggregate pores greater than 6 μm. However, loading saturated loess leads to transformation from a bimodal PSD into a trimodal one that defines three major pore series, namely large-pore series (i.e., more than 6 μm), medium-pore series (i.e., between 0.1 and 6 μm) and small-pore series (i.e., less than 0.1 μm). The trimodal nature of PSD is, however, destructed under higher vertical stresses. Both large pores and medium pores are compressed under higher vertical stresses (i.e., > 600 kPa). The inundating-induced change in PSD is dependent on loading condition and can be discerned to take place in the same three pore series. Not only large pores but also medium pores collapse upon inundating under higher vertical stresses (i.e., > 600 kPa). The microstructural evolution is consistent with the mechanical responses of both intact and saturated loess.

The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Merck KGaA, and Pfizer Inc.