Synthesis of gem-Difluorinated Oxa/Azaspiro[2.4]heptanes via Palladium-Catalyzed Spirocyclopropanation.

A palladium-catalyzed spirocyclopropanation of gem-difluoroalkenes with π-allylpalladium 1,4-dipoles has been successfully developed, which gives a powerful and straightforward synthetic strategy for the construction of novel gem-difluorinated spirocyclic compounds, 6,6-difluoro-5-oxa/azaspiro[2.4]heptanes. The scope of gem-difluoroalkenes can be extended to styrenes, acrylic esters, and acrylamides to realize the installment of various functional groups and different heteroatoms on the spirocyclic skeletons, which could be converted to valuable compounds with potential biological activity. The mechanistic investigations revealed the competition between spirocyclopropanation and ß-F elimination of π-allylpalladium zwitterionic intermediates.

Molybdenum-catalyzed deoxygenative heterocyclization of 2-nitroazobenzenes: a novel strategy for catalytic synthesis of 2-aryl-2H-benzo[d][1,2,3]triazoles.

A novel strategy for the catalytic synthesis of 2-aryl-2H-benzo[d][1,2,3]triazoles bearing a wide range of functional groups in good to excellent yields by non-noble molybdenum-catalyzed deoxygenative heterocyclization of 2-nitroazobenzenes is described. The salient features of the transformation include the use of readily available substrates, valuable products and ease of scale-up. The mechanistic study indicates that the reaction occurred via double deoxygenation by the Mo(VI)/Mo(IV) catalytic cycle from 2-nitroazobenzene, through the formation of 2-aryl-2H-benzo[d][1,2,3]triazole-N1-oxide or nitrene intermediates.

Palladium-catalyzed ring-opening [5+2] annulation of vinylethylene carbonates (VECs) and C5-substituted Meldrum's acids: rapid synthesis of 7-membered lactones.

A novel approach for the synthesis of unsaturated 7-membered lactones by Pd-catalyzed [5+2] dipolar cycloaddition of vinylethylene carbonates (VECs) and C5-substituted Meldrum's acid derivatives has been developed. Various Meldrum's acid derivatives worked well in this reaction under mild reaction conditions. A variety of 7-membered lactones can be accessed in a facile manner in moderate to good yields by employing easily prepared Meldrum's acid derivatives.

CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes.

In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cardiac cell hypertrophy, and cardiac fibrosis occurred in DICAR deficiency (DICAR+/-) mice, whereas the DCM was alleviated in DICAR-overexpressed DICARTg mice. At the cellular level, we found that overexpression of DICAR inhibited, but knockdown of DICAR enhanced the diabetic cardiomyocyte pyroptosis. At the molecular level, we identified that DICAR-VCP-Med12 degradation could be the underlying molecular mechanism in DICAR-mediated effects. The synthesized DICAR junction part (DICAR-JP) exhibited a similar effect to the entire DICAR. In addition, the expression of DICAR in circulating blood cells and plasma from diabetic patients was lower than that from health controls, which was consistent with the decreased DICAR expression in diabetic hearts. DICAR and the synthesized DICAR-JP may be drug candidates for DCM.

Cerebral Blood Flow Alterations in Sepsis-Associated Encephalopathy: A Prospective Observational Study.

BACKGROUND: The timely recognition of sepsis-associated encephalopathy (SAE) remains a challenge. This study aimed to observe the CBF changes via TCD during sepsis and explore their possible predictive value in SAE. METHODS: In this prospective observational study, septic patients were enrolled and classified according to the diagnosis of SAE into two groups: SAE group and non-SAE group. Then SAE patients were further divided into subgroup A (the type with agitation) and subgroup B (the type with depressed consciousness) based on their clinical manifestations. The clinical profiles and TCD parameters within 24 hours of onset were compared between groups and subgroups. RESULTS: Exactly 198 septic patients were enrolled including 65 patients in SAE group (36 male/29 female with a median age of 70) and 133 patients in non-SAE group (75 male/58 female with a median age of 67). Significant elevated peak-systolic velocity (VS; 107 [69-138] cm/s vs 85 [69-101] cm/s, P = .002) of the left middle cerebral artery (MCA) and pulsatility index (PI; left: 0.99 [0.81-1.34] vs 0.89 [0.76-1.00], P < .001; right: 0.99 [0.77-1.21] vs 0.88 [0.78-1.03], P = .007) of bilateral MCAs were found in SAE group compared with non-SAE group. In subgroup analysis, subgroup A (the type with agitation) showed significantly increased VS/VM/VD and lower PI/RI of bilateral MCAs compared with subgroup B (the type with depressed consciousness). The cerebral blood flow volume of subgroup A were obviously higher than subgroup B [858.7 (729.1,876.9) mL/s vs 380.9 (373.3,447.4) mL/s, P < .001]. CONCLUSIONS: This study confirmed the abnormal CBF among SAE and found different types of CBF alterations were related to different clinical features. VS and PI might help clinicians to early identify different types of SAE.

Single-fraction SRS and multiple-fraction SRT for brain metastases from colorectal cancer.

Objective: Brain metastasis from colorectal cancer (CRC) is rare. Although stereotactic radiotherapy (SRT) and stereotactic radiosurgery (SRS) are effective treatments for brain metastasis, reports on brain metastasis of CRC are limited. This study compared the efficacy of SRT and SRS for the treatment of brain metastases from CRC and analysed the related factors to reveal the specificity CRC-derived brain metastasis. Methods: A retrospective analysis of 116 patients with brain metastases from colorectal cancer was performed and included 56 patients in the SRT group and 60 patients in the SRS group. The clinical characteristics of the two groups were analysed, and the local tumour control rate, overall survival time and radiation-induced brain injury were compared between the two groups. Results: The objective response rates of the SRT and SRS groups were 76.8% and 66.7%, respectively, while the local control rates at 6 months were 87.5% and 81.6%, respectively, and no significant differences were observed between the groups (P=0.295). The median overall survival time was 10.3 months for all patients and was 10.9 months in the SRT group and 9.8 months in the SRS group, with no significant difference between the groups (P=0.123). A multivariate analysis showed that the main factors of poor prognosis were low GPA score (P=0.002), KRAS mutation (P=0.035), extracranial metastasis (P=0.005) and no bevacizumab treatment (P=0.001). No significant difference was observed in the incidence of acute and late radiation-induced injury between the two groups. Conclusion: Both SRT and SRS are effective methods for the treatment of CRC-derived brain metastases. The simultaneous use of bevacizumab may be one of the most important factors that affects the survival of these patients.

Tumor-triggered targeting ammonium bicarbonate liposomes for tumor multimodal therapy.

Tumor-triggered targeting ammonium bicarbonate (TTABC) liposomes were proposed to improve the uptake of ammonium bicarbonate (ABC) liposomes in tumor cells and retain their long circulation in vivo in our previous study. However, it must be solved how to precisely release the loaded drugs of the TTABC liposomes into tumor cells. In addition, synergistic multimodal therapy could result in better tumor treatment outcomes than monomodal chemotherapy. In the research, we prepared indocyanine green (ICG) and doxorubicin (DOX) encapsulated TTABC liposomes (ICG&DOX@TTABC) to achieve near-infrared (NIR) light-controlled chemo/photothermal/photodynamic multimodal therapy guided by fluorescence and photothermal imaging. In vitro and vivo studies show that ICG&DOX@TTABC can specifically accumulate in tumor tissues, effectively transform NIR light into local thermo-therapy, and have excellent anti-tumor ability without obvious side effects. ICG&DOX@TTABC could be promising for fluorescence and photothermal imaging-guided chemo/photothermal/photodynamic tumor treatment.

Developing Flexible Quinacridone-Derivatives-Based Photothermal Evaporaters for Solar Steam and Thermoelectric Power Generation.

Solar-driven interfacial vaporization by localizing solar-thermal energy conversion to the air-water interface has attracted tremendous attention. In the process of converting solar energy into heat energy, photothermal materials play an essential role. Herein, a flexible solar-thermal material di-cyan substituted 5,12-dibutylquinacridone (DCN-4CQA)@Paper was developed by coating photothermal quinacridone derivatives on the cellulose paper. The DCN-4CQA@Paper combines desired chemical and physical properties, broadband light-absorbing, and shape-conforming abilities that render efficient photothermic vaporization. Notably, synergetic coupling of solar-steam and solar-electricity technologies by integrating DCN-4CQA@Paper and the thermoelectric devices is realized without trade-offs, highlighting the practical consideration toward more impactful solar heat exploitation. Such solar distillation and low-grade heat-to-electricity generation functions can provide potential opportunities for fresh water and electricity supply in off-grid or remote areas.

Design and analysis of three-dimensional printing of a porous titanium scaffold.

OBJECTIVE: Mechanic strength, pore morphology and size are key factors for the three-dimensional (3D) printing of porous titanium scaffolds, therefore, developing optimal structure for the 3D printed titanium scaffold to fill bone defects in knee joints is instructive and important. METHODS: Structural models of titanium scaffolds with fifteen different pore unit were designed with 3D printing computer software; five different scaffold shapes were designed: imitation diamond-60°, imitation diamond-90°, imitation diamond-120°, regular tetrahedron and regular hexahedron. Each structural shape was evaluated with three pore sizes (400, 600 and 800 µm), and fifteen types of cylindrical models (size: 20 mm; height: 20 mm). Autodesk Inventor software was used to determine the strength and safety of the models by simulating simple strength acting on the knee joints. We analyzed the data and found suitable models for the design of 3D printing of porous titanium scaffolds. RESULTS: Fifteen different types of pore unit structural models were evaluated under positive pressure and lateral pressure; the compressive strength reduced when the pore size increased. Under torsional pressure, the strengths of the imitation diamond structure were similar when the pore size increased, and the strengths of the regular tetrahedron and regular hexahedron structures reduced when the pore size increased. In each case, the compressive strength of the regular hexahedron structure was highest, that of the regular tetrahedron was second highest, and that of the imitation diamond structure was relatively low. Fifteen types of cylindrical models under a set force were evaluated, and the sequence of comprehensive compressive strength, from strong to weak was: regular hexahedron > regular tetrahedron > imitation diamond-120° > imitation diamond-90° > imitation diamond-60°. The compressive strength of cylinder models was higher when the pore size was smaller. CONCLUSION: The pore size and pore morphology were important factors influencing the compressive strength. The strength of each structure reduced when the pore size (400, 600 and 800 µm) increased. The models of regular hexahedron, regular tetrahedron and imitation diamond-120°appeared to meet the conditions of large pore sizes and high compressive strength.

An aryl thiol-vinyl azide coupling reaction and a thiol-vinyl azide coupling/cyclization cascade: efficient synthesis of ß-ketosulfides and arene-fused 5-methylene-2-pyrrolidinone derivatives.

The addition reaction of thiol to vinyl azide has been extensively studied. Variously substituted aryl thiols are all viable for this coupling process. The scope of the other partner is successfully expanded from α-aryl vinyl azide to α-alkyl vinyl azide. A thiol-vinyl azide coupling/cyclization cascade is realized with substituted aryl vinyl azides carrying a 2-methoxycarbonyl group. The value of ß-ketosulfide products was demonstrated by its application in S-heterocycle synthesis.

Hydrogen gas protects against delayed encephalopathy after acute carbon monoxide poisoning in a rat model.

Objective: The protective effects of 2%-4% hydrogen gas in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) have been previously reported. This study aimed to assess the neuroprotective effects of high concentration hydrogen (HCH) on DEACMP.Methods: A total of 36 male Sprague-Dawley rats were divided into 3 groups. In the DEACMP group, rats were exposed to CO to induce CO poisoning; in the HCH group, the animals were exposed to 67% H2 and 33% O2 at 3,000 mL/min for 90 min immediately after CO poisoning. Neurological function was evaluated at 1 and 9 days after poisoning. Then, the contents of malondialdehyde, 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine, as well as superoxide dismutase activity in the serum, cortex and hippocampus were detected by ELISA. Additionally, the mRNA and protein expression levels of Nrf2 and downstream genes were detected by RT-PCR and Western blotting, respectively.Results: Our results showed that CO poisoning significantly impaired neurological function which was improved over time, and HCH markedly attenuated neurological impairment following CO poisoning. In addition, CO poisoning resulted in increased levels of malondialdehyde, 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine and markedly reduced superoxide dismutase activity at 1 and 9 days, which were significantly inhibited by HCH at 9 days. Finally, CO poisoning increased the mRNA and protein levels of Nrf2 and downstream genes, and HCH further induced the anti-oxidative capability.Conclusion: These findings indicate the neuroprotective effects of HCH on DEACMP, which are related to the activation of Nrf2 signaling pathway.

Mindfulness-based stress reduction improves the general health and stress of Chinese military recruits: A pilot study.

This paper reported the health effects of mindfulness-based stress reduction (MBSR) among 49 Chinese military recruits with psychological distress in a 12-week study. Participants were randomized into a MBSR and a waitlist group. Previously validated questionnaires were administered to both groups at four time points: baseline, 5, 8, and 12 weeks after participation. Compared to the waitlist group, the MBSR group showed more improvements in mindfulness and general health, as well as more stress reduction at 12-week follow-up. This study suggested that MBSR could be a promising health intervention for improving general health and reducing stress in Chinese military recruits.

Intramolecular Imino-ene Reaction of Azirines: Regioselectivity, Diastereoselectivity, and Computational Insights.

Intramolecular imino-ene reaction of 2 H-aziridine has been studied experimentally and computationally, demonstrating that (1) the concerted process takes place regioselectively on the alkene E-CH group; (2) the geometry of the N-linker impacts the reaction activation energy and diastereoselectivity significantly, with pyramidal alkyl amine as the linkage, an exclusive cis-product is achieved; (3) when the reaction has to occur with the Z-CH group, the cis-diastereoselectivity is solely observed regardless of the nature of the N-linkage.

Stereoselective synthesis of all-cis boryl tetrahydroquinolines via copper-catalyzed regioselective addition/cyclization of o-aldiminyl cinnamate with B2Pin2.

A copper catalyzed intramolecular 1,2-carboboration of o-aldiminyl cinnamate has been realized in both regio- and stereoselective fashions. This reaction provides a convenient entry to highly valuable and otherwise challenging cis-2,3,4-trisubstituted tetrahydroquinolines carrying a 4-boryl group. An unusual non-Michael addition intermediate or alternatively, a cyclic enolate is proposed to account for the intriguing all-cis configuration in the final products.

Defective Treg response in acute kidney injury was caused by a reduction in TIM-3+ Treg cells.

BACKGROUND: Despite years of research, the treatment of acute kidney injury (AKI) remains a significant challenge. Animal studies presented causal links between elevated regulatory T cell (Treg) response and better prognosis in AKI. Previous studies in mice and humans showed that TIM-3+ Treg cells were more potent than TIM-3- Treg cells. In this study, we investigated the role of TIM-3 in Treg in AKI patients. METHODS: Peripheral blood from AKI patients and healthy controls were gathered, and TIM-3+ Treg subset was examined. RESULTS: Compared to healthy controls, the AKI patients presented a significant upregulation in the frequency of circulating CD4+CD25+ T cells; however, the majority of this increase was from the CD4+CD25+TIM-3- subset, and the frequency of CD4+CD25+TIM-3+ T cells was downregulated in AKI patients. In both healthy controls and AKI patients, the CD4+CD25+TIM-3+ T cells expressed higher levels of Foxp3, and were more potent at expressing LFA-1, LAG-3, CTLA-4, IL-10 and TGF-ß. In addition, the CD4+CD25+TIM-3+ T cells from both healthy controls and AKI patients presented higher capacity to suppress CD4+CD25- T cell proliferation than the CD4+CD25+TIM-3- T cells. Interestingly, the total CD4+CD25+ T cells from AKI patients presented significantly lower inhibitory capacity than those from healthy controls, indicating that the low frequency of CD4+CD25+TIM-3+ T cells was restricting the efficacy of the Treg responses in AKI patients. CONCLUSIONS: We demonstrated that TIM-3 downregulation impaired the function of Treg cells in AKI. The therapeutic potential of CD4+CD25+TIM-3+ T cells in AKI should be investigated in future studies.

Intramolecular Imino-ene Reaction of 2H-azirines with Alkenes: Rapid Construction of Spiro NH Aziridines from Vinyl Azides.

A range of novel (poly)cyclic alkaloids incorporating an unprecedented 1,5-diazaspiro[2.4]heptane core that carry a spiro NH aziridine moiety and a 7-vinyl group are constructed from the thermal reaction of vinyl azides with tethered alkenes. Vinyl azides are converted to 2H-azirines in situ, which serve as enophiles for intramolecular imino-ene reactions with suitable alkenes. High stereoselectivity and specificity have been achieved for this novel intramolecular imino-ene reaction of azirines.

Copper-Catalyzed Borylative Cyclization of Substituted N-(2-Vinylaryl)benzaldimines.

A t-BuOCu-initiated reaction sequence of styrene borometalation and intramolecular imine addition has been achieved using a Cu(OTf)2/dppf combination as catalyst. The product of this reaction cascade is a useful 2,3-disubstituted indoline bearing a versatile boryl moiety and is formed with sole cis-selectivity. To account for the observation of the exclusive formation of cis-stereoisomers, a transition state featuring copper-imine coordination is suggested. The application to the synthesis of antioxidant tetrahydroindenoindoles is described.

Intramolecular Schmidt Reaction of Vinyl Azides with Cyclic Ketones.

Cyclic ketones tethered with a vinyl azide group undergo a Schmidt-hydrolysis sequence to give secondary lactams bearing a ketone side chain. Secondary lactams are obtained in a regioselective manner that is not possible in a conventional Schimdt reaction. In addition to the well-documented C-2 nucleophilicity, the N nucleophilicity of vinyl azide disclosed in this work opens a new direction for reaction invention involving vinyl azides.

Comamonas kerstersii bacteremia in a patient with acute perforated appendicitis: A rare case report.

RATIONALE: Comamonas species are rarely associated with human infections. Recent reports found that Comamonas kerstersii was associated with severe diseases such as abdominal infection and bacteremia. However, C. kerstersii maybe be confused with Comamonas testosteroni using the automatic bacterial identification systems currently available. PATIENT CONCERNS: A 31-year-old man who had onset of left upper abdominal pain developed clinical manifestations of right lower abdominal pain and classic migration of pain at the temperature of 39°C. The positive strain of aerobic and anaerobic bottles of blood cultures was identified. DIAGNOSES: The patient was diagnosed as acute peritonitis and perforated appendix with abdominal abscess. INTERVENTIONS: The bacterium was identified by routine methods, MALDI-TOF-MS and PCR amplification of the 16S rRNA. The patient was treated with exploratory laparotomy, appendectomy, tube drainage, and prescribing antibiotic treatment. OUTCOMES: The patients were discharged with complete recovery. The organisms were confirmed as C. kerstersii by MALDI-TOF-MS and a combination of the other results. LESSONS: Our findings suggest that C. kerstersii infection occurs most often in association with perforated appendix and bacteremia. We presume that C. kerstersii is an opportunistic pathogen or commensal with the digestive tract and appendix bacteria.

Selective S-arylation of 2-oxazolidinethiones and selective N-arylation of 2-benzoxazolinones/2-benzimidazolinones.

There exist three possible patterns for the reaction of cyclic 2-oxazolidinethione and 2-benzoxazolidinethione with arynes, namely (a) S-arylation, (b) N-arylation, and (c) aryne insertion into the thiocarbonyl group (C[double bond, length as m-dash]S). Our studies demonstrate that S-arylation wins out affording S-aryl dihydrooxazoles. In contrast, for related reactions of cyclic 2-benzoxazolinone and 2-benzimidazolinone with arynes, it is found that N-arylation outcompetes O-arylation and aryne insertion into the C[double bond, length as m-dash]O group to give N-aryl 2-benzoxazolinones and N-aryl 2-benzimidazolinones.