Difluoromethylation-Carboxylation and -Deuteration of Alkenes Triggered by Electroreduction of Difluoromethyltriphenylphosphonium Bromide.

It is significant to develop novel difluoromethylation methods because of the important roles of difluoromethyl groups in the medicinal chemistry and material industries. Here, we developed a novel difluoromethylation-carboxylation and difluoromethylation-deuteration method triggered by a difluoromethyl radical generated by electroreduction of stable and easily available difluoromethyltriphenylphosphonium bromide. Various molecules containing difluoromethyl and carboxyl or deuterium groups can be synthesized through this method. The establishment of this method will provide an alternative to radical difluoromethylation reactions.

Photoredox Metal-Free Synthesis of Unnatural ß-Silyl-α-Amino Acids via Hydrosilylation.

An efficient, practical and metal-free methodology for the synthesis of ß-silyl-α-amino acid motifs via photoredox and hydrogen atom transfer (HAT) process is described. This protocol enables the direct hydrosilylation of dehydroalanine derivatives and tolerates a wide array of functional groups and synthetic handles, leading to valuable ß-silyl-α-amino acids with moderate to good yields.

Magnesium-Mediated Umpolung Carboxylation of p-Quinone Methides with CO2.

Magnesium-mediated reductive carboxylation of p-QMs with CO2 via an Umpolung strategy has been developed, which can be used for the preparation of various aryl acetic acids. This protocol featured high atom economy, mild conditions, and operational simplicity. The creation of this Umpolung carboxylation of p-QMs will unprecedentedly extend the application of p-QMs to nucleophilic reagents.

Thrust generation and propulsive efficiency in dolphin-like swimming propulsion.

Given growing interest in emulating dolphin morphology and kinematics to design high-performance underwater vehicles, the current research effort is dedicated to studying the hydrodynamics of dolphin-like oscillatory kinematics in forward propulsion. A computational fluid dynamics method is used. A realistic three-dimentional surface model of a dolphin is made with swimming kinematics reconstructed from video recording. The oscillation of the dolphin is found to enhance the attachment of the boundary layer to the posterior body, which then leads to body drag reduction. The flapping motion of the flukes is found to generate high thrust forces in both the downstroke and the upstroke, during which vortex rings are shed to produce strong thrust jets. The downstroke jets are found to be on average stronger than the upstroke jet, which then leads to net positive lift production. The flexion of the peduncle and flukes is found to be a crucial feature of dolphin-like swimming kinematics. Dolphin-inspired swimming kinematics were created by varying the flexion angle of the peduncle and flukes, which then resulted in significant performance variation. The thrust benefits and propulsive efficiency benefits are associated with a slight decrease and slight increase of the flexion of the peduncle and flukes, respectively.

m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice.

Different organs undergo distinct transcriptional, epigenetic and physiological alterations that guarantee their functional maturation after birth. However, the roles of epitranscriptomic machineries in these processes have remained elusive. Here we demonstrate that expression of RNA methyltransferase enzymes Mettl3 and Mettl14 gradually declines during postnatal liver development in male mice. Liver-specific Mettl3 deficiency causes hepatocyte hypertrophy, liver injury and growth retardation. Transcriptomic and N6-methyl-adenosine (m6A) profiling identify the neutral sphingomyelinase, Smpd3, as a target of Mettl3. Decreased decay of Smpd3 transcripts due to Mettl3 deficiency results in sphingolipid metabolism rewiring, characterized by toxic ceramide accumulation and leading to mitochondrial damage and elevated endoplasmic reticulum stress. Pharmacological Smpd3 inhibition, Smpd3 knockdown or Sgms1 overexpression that counteracts Smpd3 can ameliorate the abnormality of Mettl3-deficent liver. Our findings demonstrate that Mettl3-N6-methyl-adenosine fine-tunes sphingolipid metabolism, highlighting the pivotal role of an epitranscriptomic machinery in coordination of organ growth and the timing of functional maturation during postnatal liver development.

The Interactive Effects of Deficit Irrigation and Bacillus pumilus Inoculation on Growth and Physiology of Tomato Plant.

The effects of inoculating plant growth promoting rhizobacteria (PGPR) and soil water deficits on crop growth and physiology remain largely unknown. Here, the responses of leaf gas exchange, growth, and water use efficiency (WUE) of tomato plants to Bacillus pumilus (B.p.) inoculation under four irrigation strategies (I1-I4) were investigated in a greenhouse. Results showed that soil water deficits, especially at I4 (20%, v/v), significantly decreased leaf stomatal conductance (gs), transpiration rate (Tr), and photosynthetic rate (An), and the decrease of gs and Tr were more pronounced than An. Reduced irrigation regimes significantly lowered dry matter and plant water use both in the non-B.p. control and the B.p. plants, while reduced irrigation significantly increased plant WUE, and B.p. inoculation had little effect on this parameter. Synergistic effects of PGPR and deficit irrigation on leaf gas exchange, leaf abscisic acid content, and stomatal density were found in this study, and specifically, B.p. treated plants at I4 possessed the highest WUE at stomatal and leaf scales, suggesting that B.p. inoculation could optimize water use and partly alleviate the negative effects of soil water deficit. These findings provide useful information for effective irrigation management and the application of PGPR in agriculture in the future.

Efficacy and cost of double filtration plasmapheresis in severe hypertriglyceridemia-induced pancreatitis: A retrospective observational study.

BACKGROUND: The value of double filtration plasmapheresis (DFPP) in severe hypertriglyceridemia-induced pancreatitis (sHTGP) is controversial. This study aimed to investigate the efficacy of DFPP on clinical outcomes in patients with sHTGP and the costs associated with the procedure. METHODS: Patients who underwent DFPP after admission between January 2016 and December 2021 were recruited. Data on lipid profile, clinical parameters, and costs were retrospectively collected and analyzed. RESULTS: Fifty sHTGP patients who received DFPP were enrolled. All of the lipid profile were significantly reduced and maintained a downward trend. The APACHE II score on admission was higher and the reduction after DFPP was more obvious (P < 0.05) in patients with higher triglyceride (TG) levels (≥33.9 mmol/L) than in patients with lower TG levels. More material fees were expended in the higher TG group due to more DFPP sessions (P < 0.05), but no significant differences existed in total hospital costs between the two groups. CONCLUSION: DFPP could rapidly and effectively reduce TGs to a safe level. APACHE II score reduction was obvious in patients with TGs ≥33.9 mmol/L and was associated with lipid profile changes. DFPP may benefit sHTGP patients with a TG level higher than the current initiation threshold.

Clinical effects of fractional carbon dioxide laser combined with minimally invasive scar release in the treatment of post-acne atrophic scars / 中华烧伤杂志

Objective: To explore the clinical effects of fractional carbon dioxide laser combined with minimally invasive scar release in the treatment of post-acne atrophic scars. Methods: A retrospectively observational study was conducted. From January to June 2021, 60 patients with grade 3 and 4 post-acne atrophic scars who met the inclusion criteria were admitted to the First Affiliated Hospital of Henan University of Traditional Chinese Medicine. According to the adopted treatment methods, 30 patients treated with fractional carbon dioxide laser combined with minimally invasive scar release were included in combined treatment group (19 males and 11 females, aged (26±4) years), and 30 patients treated with fractional carbon dioxide laser alone were included in laser alone group (18 males and 12 females, aged (25±6) years). All the patients received the treatment once every two months, totally 3 times. Before the first treatment and 2 months after the last treatment, the scars were assessed by échelle d'évaluation clinique des cicatrices d'acné (ECCA). In 2 months after the last treatment, the curative effect was evaluated and the total effective rate was calculated according to the ECCA score. The adverse reactions of patients during the treatment were recorded. Data were statistically analyzed with independent sample t test, Wilcoxon rank-sum test, Mann-Whitney U test, chi-square test, and Fisher's exact probability test. Results: Before the first treatment, the ECCA scores of patients in the two groups were similar (P>0.05). In 2 months after the last treatment, the ECCA scores of patients in combined treatment group were significantly lower than those of laser alone group (Z=-2.89, P<0.05). The ECCA scores of patients in combined treatment group and laser alone group in 2 months after the last treatment were both significantly lower than those before the first treatment (with Z values of -4.81 and -4.79, respectively, P<0.05). In 2 months after the last treatment, the treatment in laser alone group cured the scars in 2 patients, and were markedly effective in 13 patients, effective in 7 patients, and ineffective in 8 patients; the treatment in combined treatment group cured the scars in 4 patients, and were markedly effective in 22 patients, effective in 3 patients, and ineffective in one patients. The total effective rate of scar treatment in combined treatment group (96.67%, 29/30) was significantly higher than 73.33% (22/30) in laser alone group (P<0.05). During treatment, in combined treatment group, 3 patients had pain, one patient had redness and swelling, and one patient had pigmentation. In laser alone group, one patient had pain, and 2 patients had pigmentation. No infection occurred in the wounds of all the patients in the two groups. Conclusions: Compared with fractional carbon dioxide laser alone, fractional carbon dioxide laser combined with minimally invasive scar release for post-acne atrophic scars can result in a higher total effective rate, with simple operation and good effect, so it is worthy of clinical application.

LRP1-Mediated Endocytosis May Be the Main Reason for the Difference in Cytotoxicity of Curcin and Curcin C on U2OS Osteosarcoma Cells.

Curcin and Curcin C, both of the ribosome-inactivating proteins of Jatropha curcas, have apparent inhibitory effects on the proliferation of osteosarcoma cell line U20S. However, the inhibitory effect of the latter is 13-fold higher than that of Curcin. The mechanism responsible for the difference has not been studied. This work aimed to understand and verify whether there are differences in entry efficiency and pathway between them using specific endocytosis inhibitors, gene silencing, and labeling techniques such as fluorescein isothiocyanate (FITC) labeling. The study found that the internalization efficiency of Curcin C was twice that of Curcin for U2OS cells. More than one entering pathway was adopted by both of them. Curcin C can enter U2OS cells through clathrin-dependent endocytosis and macropinocytosis, but clathrin-dependent endocytosis was not an option for Curcin. The low-density lipoprotein receptor-related protein 1 (LRP1) was found to mediate clathrin-dependent endocytosis of Curcin C. After LRP1 silencing, there was no significant difference in the 50% inhibitory concentration (IC50) and endocytosis efficiency between Curcin and Curcin C on U2OS cells. These results indicate that LRP1-mediated endocytosis is specific to Curcin C, thus leading to higher U2OS endocytosis efficiency and cytotoxicity than Curcin.

Spatially Confined Face-Selective Growth of Large-Area 2D Organic Molecular Crystals in a Supramolecular Gel for Highly Efficient Flexible Photodetection.

2D organic molecular crystals (2DOMCs) are promising materials for the fabrication of high-performance optoelectronic devices. However, the growth of organic molecules into 2DOMCs remains a challenge because of the difficulties in controlling their self-assembly with a preferential orientation in solution-process crystallization. Herein, fullerene is chosen as a model molecule to develop a supramolecular gel crystallization approach to grow large-area 2DOMCs by controlling the perfect arrangement on the {220} crystal plane with the assistance of a gelated solvent. In this case, the gel networks provide tuneable confined spaces to control the crystallization kinetics toward the growth of dominant crystal faces by their inhibiting motions of solvent or solute molecules to enable the growth of perfect crystals at appropriate nucleation rates. As a result, a large-area fullerene 2DOMC is produced successfully and its corresponding device on a flexible substrate exhibits excellent bendable properties and ultra-high weak light detection ability (2.9 × 1011 Jones) at a 10 V bias upon irradiation with 450 nm incident light. Moreover, its photoelectric properties remain unchanged after 200 cycles of bending at angles of 45, 90, and 180°. These results can be extended to the growth of other 2DOMCs for potentially fabricating advanced organic (opto)electronics.

Photoredox Metal-Free Allylic Defluorinative Silylation of α-Trifluoromethylstyrenes with Hydrosilanes.

We report an efficient strategy that combines organic photoredox and hydrogen atom transfer to deliver gem-difluoroallylsilanes via defluorinative silylation of α-trifluoromethylstyrenes using hydrosilanes as silicon sources. This protocol provides an environmentally friendly approach for the preparation of structurally diverse gem-difluoroallylsilanes with excellent functional group compatibility and renders it suitable for late-stage modification of bioactive and complex molecules.

Extracorporeal Membrane Oxygenation-First Strategy for Acute Life-Threatening Pulmonary Embolism.

Background: Both venoarterial extracorporeal membrane oxygenation (VA-ECMO) and percutaneous mechanical thrombectomy (PMT) are increasingly used to treat acute life-threatening pulmonary embolism (PE). However, there are little data regarding their effectiveness. This study aimed to present the short-term outcomes after managing nine patients with acute life-threatening massive or submassive PE by VA-ECMO with or without complemented PMT and propose a preliminary treatment algorithm. Methods: This study was a single-center retrospective review of a prospectively maintained registry. It included nine consecutive patients with massive or submassive pulmonary embolism who underwent VA-ECMO for initial hemodynamic stabilization, with or without PMT, from August 2018 to November 2021. Results: Mean patient age was 54.7 years. Four of nine patients (44.4%) required cardiopulmonary resuscitation before or during VA-ECMO cannulation. All cannulations (100%) were successfully performed percutaneously. Overall survival was 88.9% (8 of 9 patients). One patient died from a hemorrhagic stroke. Of the survivors, the median ECMO duration was 8 days in patients treated with ECMO alone and 4 days in those treated with EMCO and PMT. Five of nine patients (55.6%) required concomitant PMT to address persistent right heart dysfunction, with the remaining survivors (44.4%) receiving VA-ECMO and anticoagulation alone. For survivors receiving VA-ECMO plus PMT, median hospital lengths of stay were 7 and 13 days, respectively. Conclusions: An ECMO-first strategy complemented with PMT can be performed effectively and safely for acute life-threatening massive or submassive PE. VA-ECMO is feasible for initial stabilization, serving as a bridge to therapy primarily in inoperable patients with massive PE. Further evaluation in a larger cohort of patients is warranted to assess whether VA-ECMO plus PMT may offer an alternative or complementary therapy to thrombolysis or surgical thrombectomy. Type of Research: Single-center retrospective review of a prospectively maintained registry.

Photocatalytic Synthesis of Diarylmethyl Silanes via 1,6-Conjugate Addition of Silyl Radicals to p-Quinone Methides.

A novel photocatalytic method for the preparation of diarylmethyl silanes was reported through silyl radicals addition strategy to p-QMs (p-quinone methides). This protocol could tolerate a variety of functional groups affording the corresponding silylation products with moderate to excellent yields. The resulting silylation products could be easily converted into a series of bioactive GPR40 agonists and useful p-QMs precursors for the synthesis of compounds possessing both quaternary carbon centers and silicon substituents through simple operation. A plausible mechanism of silyl radicals to p-QMs was proposed on the basis of experimental results and previous literature.

Curcin C inhibit osteosarcoma cell line U2OS proliferation by ROS induced apoptosis, autophagy and cell cycle arrest through activating JNK signal pathway.

Osteosarcoma is a kind of primary bone malignant tumors. Its cure rate has been stagnant in the past decade years. Curcin C belongs to type I ribosome inactivating proteins, extracted from the cotyledons of post-germinated Jatropha curcas seeds. It can inhibit the proliferation of several tumor lines including U2OS cells with extraordinary efficiency. The treated U2OS cells were arrested in both S and G2/M phase, showed typical apoptosis morphological characteristic, formed autophagosomes and increase the ratio of LC3II to LC3I. Meanwhile, the level of ROS in the treated cells was found increasing significantly, with the change of mitochondrial membrane potential and decreased antioxidant enzyme activities. The application of ROS scavenger NAC not only significantly inhibited the toxicity of Curcin C but also prevented the happen of apoptosis and autophagy to some extent. These results suggested that Curcin C may function through ROS pathway. In addition, the Curcin C treatment could activate JNK and inhibit ERK signal pathway. Sp600125, an inhibitor of JNK signaling pathway, can prevent subsequent apoptosis and autophagy events, suggesting that JNK pathway was at least one of the pathways of Curcin C action. Moreover, the relevant including antagonistic among autophagy, apoptosis and cell cycle arresting induced by Curcin C also was found. In summary, it can be speculated that Curcin C may induce S, G2/M phase arrest, apoptosis and autophagy of human osteosarcoma U2OS cells through activating JNK signal pathway and blocking ERK signal pathway by promoting ROS accumulation in cell, thus finally reflected in the effect of inhibiting tumor cell proliferation.

Abnormalities of bone marrow B cells and plasma cells in primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an autoantibody-mediated hemorrhagic disorder in which B cells play an essential role. Previous studies have focused on peripheral blood (PB), but B cells in bone marrow (BM) have not been well characterized. We aimed to explore the profile of B-cell subsets and their cytokine environments in the BM of patients with ITP to further clarify the pathogenesis of the disease. B-cell subpopulations and their cytokine/chemokine receptors were detected by using flow cytometry. Plasma concentrations of cytokines/chemokines were measured by using enzyme-linked immunosorbent assay. Messenger RNA levels of B cell-related transcription factors were determined by using quantitative polymerase chain reaction. Regulatory B cell (Breg) function was assessed by quantifying their inhibitory effects on monocytes and T cells in vitro. Decreased proportions of total B cells, naive B cells, and defective Bregs were observed in patients with ITP compared with healthy controls (HCs), whereas an elevated frequency of long-lived plasma cells was found in BM of autoantibody-positive patients. No statistical difference was observed in plasmablasts or in short-lived plasma cells between patients with ITP and HCs. The immunosuppressive capacity of BM Bregs from patients with ITP was considerably weaker than HCs. An in vivo study using an active ITP murine model revealed that Breg transfusion could significantly alleviate thrombocytopenia. Moreover, overactivation of CXCL13-CXCR5 and BAFF/APRIL systems were found in ITP patient BM. Taken together, B-cell subsets in BM were skewed toward a proinflammatory profile in patients with ITP, suggesting the involvement of dysregulated BM B cells in the development of the disease.

Comparison of Success Rate and Complications of Totally Percutaneous Decannulation in Patients With Veno-Arterial Extracorporeal Membrane Oxygenation and Endovascular Aneurysm Repair.

Background: Total percutaneous closure for the site of femoral arterial puncture using Perclose ProGlide (PP) has become prevalent post-percutaneous endovascular aortic repair (EVAR) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Objective: To evaluate the safety and efficacy of total percutaneous closure of the femoral artery access site post-EVAR compared with VA-ECMO. Methods: This was a retrospective observational study conducted over 4 years, including 88 patients who underwent EVAR (64 patients) and VA-ECMO (24 patients). Perclose ProGlide devices were used in the femoral artery puncture sites closed percutaneously. In this study, technical success was defined as successful arterial closure of the common femoral artery (CFA) without additional surgical or endovascular procedures to prevent vessel leaking. Access site complications, including overt bleeding requiring transfusion or surgical intervention, minor bleeding, tinea cruris, pseudoaneurysm, and lymphocele, were recorded 24 h and 30 days after arterial closure. Results: Each group's technical success rates were 95.8% (VA-ECMO) and 92.2% EVAR, respectively. There were no differences in the periprocedural complications of major bleeding, pseudoaneurysm, minor bleeding, acute limb ischemia, and groin infection. Furthermore, we did not observe any complications such as arterial thrombosis, dissection, stenosis, arteriovenous fistula, hematoma, groin infection, or lymphocele at the access site by following-up an ultrasound examination. There was no significant difference in the technical success rate of percutaneous closure by the PP device in the EVAR and VA-ECMO oxygenation groups. Also, no periprocedural or 30-day complications were observed at the access site of the EVAR and VA-ECMO patients.

Development and validation of a triplex assay to study an antibody cocktail against Ebola virus in cynomolgus serum.

Background: To support the rapid development of an antibody cocktail against Ebola virus and avoid unnecessary exposure to infectious environments, an automatic and fast turnover triplex assay was developed using Simoa® (Quanterix Corporation, MA, USA). Materials & methods: A robust triplex assay was developed and validated for simultaneous quantification of the antibody cocktail against Ebola virus in cynomolgus serum. Results: The assay had a quantitation range of 78.1-5000 ng/ml. The intra- and interassay precisions (%CV) were within 11.4 and 13.9%, and the accuracies (%RE) were within -10.8 to 6.8%, respectively. Cross-reactivity was evaluated, and the results met the acceptance criteria. Conclusion: The assay was successfully applied to a pharmacokinetics study following a single-dose intravenous administration of 10 mg/kg the antibody cocktail against Ebola virus to cynomolgus monkeys.

One new spirocyclic lactone and one new benzopyran derivative from Aspergillus terreus.

One new spirocyclic lactone, terreinlactone C (1), and one new benzopyran derivative, 2,2-dimethyl-3-hydroxychroman-6-aldehyde (2), were discovered from the fungus Aspergillus terreus. The chemical structures of compounds 1 and 2 were elucidated by detailedly analyzing NMR and HRESIMS data. Compound 1 is the first natural product with a 1-oxaspiro[4.5]decan-2-one ring system and a possible biogenetic pathway is proposed. Two compounds were tested for their cytotoxic activities against five human cancer cell lines.[Formula: see text].

Alveolar size effects on nanoparticle deposition in rhythmically expanding-contracting terminal alveolar models.

Significant differences in alveolar size exist in humans of different ages, gender, health, and among different species. The effects of alveolar sizes, as well as the accompanying breathing frequencies, on regional and local dosimetry of inhaled nanoparticles have not been sufficiently studied. Despite a well-accepted qualitative understanding of the advection-diffusion-sedimentation mechanism in the acinar region, a quantitative picture of the interactions among these factors remains inchoate. The objective of this study is to quantify the effects of alveolar size on the regional and local deposition of inhaled nanoparticles in alveolar models of varying complexities and to understand the dynamic interactions among different deposition mechanisms. Three different models were considered that retained 1, 4, and 45 alveoli, respectively. For each model, the baseline geometry was scaled by », ½, 2, 4, and 8 times by volume. Temporal evolution and spatial distribution of particle deposition were tracked using a discrete-phase Lagrangian model. Lower retentions of inhaled nanoparticles were observed in the larger alveoli under the same respiration frequency, while similar retentions were found among different geometrical scales if breathing frequencies allometrically matched the alveolar size. Dimensional analysis reveals a manifold deposition mechanism with tantamount contributions from advection, diffusion, and gravitational sedimentation, each of which can become dominant depending on the location in the alveoli. Results of this study indicate that empirical correlations obtained from one sub-population cannot be directly applied to others, nor can they be simply scaled as a function of the alveolar size or respiration frequency due to the regime-transiting deposition mechanism that is both localized and dynamic.

Synthesis of Amide Enol Carbamates and Carbonates through Cu(OTf)2-Catalyzed Reactions of Ynamides with t-Butyl Carbamates/Carbonates.

A highly regioselective approach to access amide enol carbamates and carbonates 5a-5c', 7a-7h, and 9 was developed through Cu(OTf)2-catalyzed reactions of ynamides 4 with t-butyl carbamates 2 and 8 and t-butyl carbonates 6. Moreover, this strategy was successfully applied to generate amide enol carbamates 11a-11s and 14a-14f from imides 10 and 13 with ynamides through an N-Boc cleavage-addition ring-opening process. A range of substituents was amenable to this transformation, and the desired amide enol carbamates and carbonates were obtained in moderate to good yields.