Synthesis of alkenylphosphine oxides via Tf2O promoted addition-elimination of ketones and secondary phosphine oxides.

Herein, we describe an efficient method for the synthesis of alkenylphosphine oxides via a Tf2O promoted addition-elimination process. Various diarylphosphine oxides and alkylarylphosphine oxides react with ketones smoothly and produce alkenylphosphine oxides in moderate to excellent yields with abundant functional group compatibility. In addition, several transformations and applications of the product also demonstrate the potential value of the methodology.

Radical Esterification of Unactivated Alkenes Using Formate as Carbonyl Source.

In recent years, methyl formate has received considerable attention as an ideal and green C1 building block to synthesize carboxylic esters. However, examples of a one-step route to esters with one-carbon elongation using methyl formate as a source of methoxycarbonyl radical are still rare. Herein, we present peroxide-induced radical carbonylation of N-(2-methylallyl)benzamides with methyl formate as the precursor of methoxycarbonyl radical and RuCl3 as catalyst, affording a series of biologically valuable 4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinolinones with good tolerance and insensitivity to moisture in one pot under simple and mild conditions.

Identification of key genes unique to the luminal a and basal-like breast cancer subtypes via bioinformatic analysis.

BACKGROUND: Breast cancer subtypes are statistically associated with prognosis. The search for markers of breast tumor heterogeneity and the development of precision medicine for patients are the current focuses of the field. METHODS: We used a bioinformatic approach to identify key disease-causing genes unique to the luminal A and basal-like subtypes of breast cancer. First, we retrieved gene expression data for luminal A breast cancer, basal-like breast cancer, and normal breast tissue samples from The Cancer Genome Atlas database. The differentially expressed genes unique to the 2 breast cancer subtypes were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We constructed protein-protein interaction networks of the differentially expressed genes. Finally, we analyzed the key modules of the networks, which we combined with survival data to identify the unique cancer genes associated with each breast cancer subtype. RESULTS: We identified 1114 differentially expressed genes in luminal A breast cancer and 1042 differentially expressed genes in basal-like breast cancer, of which the subtypes shared 500. We observed 614 and 542 differentially expressed genes unique to luminal A and basal-like breast cancer, respectively. Through enrichment analyses, protein-protein interaction network analysis, and module mining, we identified 8 key differentially expressed genes unique to each subtype. Analysis of the gene expression data in the context of the survival data revealed that high expression of NMUR1 and NCAM1 in luminal A breast cancer statistically correlated with poor prognosis, whereas the low expression levels of CDC7, KIF18A, STIL, and CKS2 in basal-like breast cancer statistically correlated with poor prognosis. CONCLUSIONS: NMUR1 and NCAM1 are novel key disease-causing genes for luminal A breast cancer, and STIL is a novel key disease-causing gene for basal-like breast cancer. These genes are potential targets for clinical treatment.

Enhanced Binding Affinity for an i-Motif DNA Substrate Exhibited by a Protein Containing Nucleobase Amino Acids.

Several variants of a nucleic acid binding motif (RRM1) of putative transcription factor hnRNP LL containing nucleobase amino acids at specific positions have been prepared and used to study binding affinity for the BCL2 i-motif DNA. Molecular modeling suggested a number of amino acids in RRM1 likely to be involved in interaction with the i-motif DNA, and His24 and Arg26 were chosen for modification based on their potential ability to interact with G14 of the i-motif DNA. Four nucleobase amino acids were introduced into RRM1 at one or both of positions 24 and 26. The introduction of cytosine nucleobase 2 into position 24 of RRM1 increased the affinity of the modified protein for the i-motif DNA, consistent with the possible Watson-Crick interaction of 2 and G14. In comparison, the introduction of uracil nucleobase 3 had a minimal effect on DNA affinity. Two structurally simplified nucleobase analogues (1 and 4) lacking both the N-1 and the 2-oxo substituents were also introduced in lieu of His24. Again, the RRM1 analogue containing 1 exhibited enhanced affinity for the i-motif DNA, while the protein analogue containing 4 bound less tightly to the DNA substrate. Finally, the modified protein containing 1 in lieu of Arg26 also bound to the i-motif DNA more strongly than the wild-type protein, but a protein containing 1 both at positions 24 and 26 bound to the DNA less strongly than wild type. The results support the idea of using nucleobase amino acids as protein constituents for controlling and enhancing DNA-protein interaction. Finally, modification of the i-motif DNA at G14 diminished RRM1-DNA interaction, as well as the ability of nucleobase amino acid 1 to stabilize RRM1-DNA interaction.

Global detection of live virtual machine migration based on cellular neural networks.

In order to meet the demands of operation monitoring of large scale, autoscaling, and heterogeneous virtual resources in the existing cloud computing, a new method of live virtual machine (VM) migration detection algorithm based on the cellular neural networks (CNNs), is presented. Through analyzing the detection process, the parameter relationship of CNN is mapped as an optimization problem, in which improved particle swarm optimization algorithm based on bubble sort is used to solve the problem. Experimental results demonstrate that the proposed method can display the VM migration processing intuitively. Compared with the best fit heuristic algorithm, this approach reduces the processing time, and emerging evidence has indicated that this new approach is affordable to parallelism and analog very large scale integration (VLSI) implementation allowing the VM migration detection to be performed better.

Seismic performance and resilience of composite damping self-centering braced frame structures.

A magnetorheological self-centering brace (MR-SCB) has been proposed to improve the energy dissipation capability of the brace. In this paper, a 15-story MR-SCB braced frame is numerically analyzed to examine its seismic performance and resilience. The MR-SCB provides higher lateral stiffness than the buckling restrained brace and greater energy dissipation capability than the existing self-centering brace. The brace also exhibits a reliable recentering capacity. Under rare earthquakes, the maximum average residual deformation ratio of the structure is less than the 0.5% limit. Under mega earthquakes, the maximum average interstory drift ratio of the structure does not exceed the 2.0% elastoplastic limit, and its maximum average floor acceleration ratio is 1.57. The effects of mainshock and aftershock on the structural behavior are also investigated. The interstory drift and residual deformation of the structure increase with the increase of the intensity of the aftershock. Under aftershocks with the same intensity as the mainshocks, the maximum increment of the residual deformation ratio of the structure is 81.8%, and the average interstory drift ratios of the 12th, 7th, and 3rd stories of the structure are increased by 13.4%, 9.2% and 7.5%, respectively. The strong aftershock may significantly cause increased damage to the structure, and increase its collapse risk and residual deformation.

Nickel-Catalyzed Deoxygenative Amidation of Alcohols with Carbamoyl Chlorides.

We report a deoxygenative amidation reaction of alcohols with carbamoyl chlorides to afford amides through nickel-photoredox dual catalysis. Good to excellent yields can be obtained even for diverse complex sugar and steroid derivatives. The reaction is scalable, and the synthetic utility of the reaction was demonstrated by the homologation of alcohols to deliver several important γ-amino alcohols and a synthetically challenging bioactive compound intermediate.

Photoredox and NHC Enabled Deoxygenative Alcohol Homologation via Formal 1,2-Addition.

A highly efficient photoinduced iron-catalyzed method has been developed for the direct use of alcohols as surrogates for organometallic reagents in the synthesis of tertiary alcohols. This method can be applied to both primary and secondary alcohols with diverse structures, enabling their reaction with aryl ketones under mild conditions. A variety of functional groups, including those that are typically reactive under conventional tertiary alcohol synthesis conditions, are compatible. Mechanistically, this reaction proceeds through the direct addition of the radical to the carbonyl pathway.

1,3-Butadiene Dicarbofunctionalization Enabled by the Dual Role of Diaryl Ketone in Photo-HAT/Chromium Catalysis.

We report a three-component Nozaki-Hiyama-Kishi type reaction of 1,3-dioxolane, 1,3-butadienes, and aldehydes to access masked aldehyde-incorporated homoallylic alcohols, facilitated by photo-hydrogen atom transfer (HAT)/chromium dual catalysis. The diaryl ketone serves dual roles both in the HAT process and in facilitating the turnover of the chromium catalyst. A range of functional groups are tolerated owing to the mild conditions. Both aromatic and aliphatic aldehydes are suitable substrates for coupling with several 1,3-butadienes and 1,3-dioxolane.

Acupuncture for generalized anxiety disorder: a study protocol for a randomized controlled trial.

During the COVID-19 outbreak, there was a sharp increase in generalized anxiety disorder (GAD). Acupuncture therapy has the advantages of accurate clinical efficacy, safety and reliability, few adverse reactions, and no dependence, and is gradually becoming one of the emerging therapies for treating GAD. We present a study protocol for a randomized clinical trial with the aim of exploring the mechanism of brain plasticity in patients with GAD and evaluate the effectiveness and reliability of acupuncture treatment. Transcranial magnetic stimulation (TMS) will be used to assess cortical excitability in GAD patients and healthy people. Sixty-six GAD patients meeting the inclusion criteria will be randomly divided into two groups: TA group, (treatment with acupuncture and basic western medicine treatment) and SA group (sham acupuncture and basic western medicine treatment). Twenty healthy people will be recruited as the control group (HC). The parameters that will be evaluated are amplitude of motor evoked potentials (MEPs), cortical resting period (CSP), resting motor threshold (RMT), and Hamilton Anxiety Scale (HAMA) score. Secondary results will include blood analysis of γ-aminobutyric acid (GABA), glutamate (Glu), glutamine (Gln), serotonin (5-HT), and brain-derived nerve growth factor (BDNF). Outcomes will be assessed at baseline and after the intervention (week 8). This study protocol is the first clinical trial designed to detect differences in cerebral cortical excitability between healthy subjects and patients with GAD, and the comparison of clinical efficacy and reliability before and after acupuncture intervention is also one of the main contents of the protocol. We hope to find a suitable non-pharmacological alternative treatment for patients with GAD.

Transcriptomic Analysis of Alternative Splicing Events during Different Fruit Ripening Stages of Coffea arabica L.

To date, genomic and transcriptomic data on Coffea arabica L. in public databases are very limited, and there has been no comprehensive integrated investigation conducted on alternative splicing (AS). Previously, we have constructed and sequenced eighteen RNA-seq libraries of C. arabica at different ripening stages of fruit development. From this dataset, a total of 3824, 2445, 2564, 2990, and 3162 DSGs were identified in a comparison of different fruit ripening stages. The largest proportion of DSGs, approximately 65%, were of the skipped exon (SE) type. Biologically, 9 and 29 differentially expressed DSGs in the spliceosome pathway and carbon metabolism pathway, respectively, were identified. These DSGs exhibited significant variations, primarily in S1 vs. S2 and S5 vs. S6, and they involve many aspects of organ development, hormone transduction, and the synthesis of flavor components. Through the examination of research findings regarding the biological functions and biochemical pathways associated with DSGs and DEGs, it was observed that six DSGs significantly enriched in ABC transporters, namely, LOC113712394, LOC113726618, LOC113739972, LOC113725240, LOC113730214, and LOC113707447, were continually down-regulated at the fruit ripening stage. In contrast, a total of four genes, which were LOC113732777, LOC113727880, LOC113690566, and LOC113711936, including those enriched in the cysteine and methionine metabolism, were continually up-regulated. Collectively, our findings may contribute to the exploration of alternative splicing mechanisms for focused investigations of potential genes associated with the ripening of fruits in C. arabica.

Fire acupuncture for plaque psoriasis case series.

OBJECTIVE: To investigate the clinical efficacy of fire acupuncture (FA) on plaque psoriasis (PP), exploring its suitable syndrome types, in order to achieve better therapeutic effects, accelerate the possibility of psoriasis skin lesion recovery, and provide assistance for clinical treatment. METHODS: A total of 8 patients with PP aged between 18 and 60 years were recruited and treated with FA once a week, and the lesion area and severity index (PASI), visual analog scale and pruritus were measured before, 2, 4 and 8 weeks after treatment and at the follow-up period (week 12), respectively. Visual analog scale, and dermoscopy were used for assessment. RESULTS: All patients showed improvement in pruritus after 1 FA treatment, and lesions were reduced to varying degrees after 2 weeks. Except for patients 5 and 8, who only achieved effective results due to severe disease, all other patients with psoriasis achieved significant results at 8 weeks after treatment. CONCLUSION: FA can significantly control the development of lesions, reduce the symptoms of PP lesions and pruritus, and help prevent psoriasis recurrence.

Copper-Catalyzed Asymmetric Cyanation of Propargylic Radicals via Direct Decarboxylation of Propargylic Carboxylic Acids.

Chiral propargylic cyanides are often used as small-molecule feedstocks for the introduction of chiral centers into various valuable products and complex molecules. Here, we have developed a highly atom-economical strategy for the chiral copper complex-catalyzed synthesis of chiral propargylic cyanides. Propargylic radicals can be smoothly obtained by direct decarboxylation of the propargylic carboxylic acids without preactivation. The reactions show excellent selectivity and functional group compatibility. Gram-scale reaction and several conversion reactions from chiral propargylic cyanide have demonstrated the synthetic value of this strategy.

Copper-Catalyzed Enantioselective Decarboxylative Cyanation of Benzylic Acids Promoted by Hypervalent Iodine(III) Reagents.

Copper-catalyzed asymmetric radical cyanation reactions have emerged as a powerful strategy for rapid construction of α-chiral nitriles. However, the directly decarboxylative cyanation reactions of common alkyl carboxylic acids remain largely elusive. Herein, we report a protocol for copper-catalyzed direct and enantioselective decarboxylative cyanation of benzylic acids. The in situ activation of acid substrates by a commercially inexpensive hypervalent iodine(III) reagent promoted the yield of the alkyl radicals under mild reaction conditions without prefunctionalization. The structurally diverse chiral alkyl nitriles were produced in good yields with high enantioselectivities. In addition, the chiral products can be readily converted to other useful chiral compounds via further transformations.

Interstitial Injection of Hydrogels with High-Mechanical Conductivity Relieves Muscle Atrophy Induced by Nerve Injury.

Injectable hydrogels have been extensively used in tissue engineering where high mechanical properties are key for their functionality at sites of high physiological stress. In this study, an injectable, conductive hydrogel is developed exhibiting remarkable mechanical strength that can withstand a pressure of 500 kPa (85% deformation rate) and display good fatigue resistance, electrical conductivity, and tissue adhesion. A stable covalent cross-linked network with a slip-ring structure by threading amino ß-cyclodextrin is formed onto the chain of a four-armed (polyethylene glycol) amino group, and then reacted with the four-armed (polyethylene glycol) maleimide under physiological conditions. The addition of silver nanowires enhances the hydrogel's electrical conductivity, enabling it to act as a good conductor in vivo. The hydrogel is injected into the fascial space, and the results show that the weight and muscle tone of the atrophied gastrocnemius muscle improve, subsequently alleviating muscle atrophy. Overall, this study provides a simple method for the preparation of a conductive hydrogel with high mechanical properties. In addition, the interstitial injection provides a strategy for the use of hydrogels in vivo.

Ubiquitous conservative interaction patterns between post-spliced introns and their mRNAs revealed by genome-wide interspecies comparison.

Introns, as important vectors of biological functions, can influence many stages of mRNA metabolism. However, in recent research, post-spliced introns are rarely considered. In this study, the optimal matched regions between introns and their mRNAs in nine model organism genomes were investigated with improved Smith-Waterman local alignment software. Our results showed that the distributions of mRNA optimal matched frequencies were highly consistent or universal. There are optimal matched frequency peaks in the UTR regions, which are obvious, especially in the 3'-UTR. The matched frequencies are relatively low in the CDS regions of the mRNA. The distributions of the optimal matched frequencies around the functional sites are also remarkably changed. The centers of the GC content distributions for different sequences are different. The matched rate distributions are highly consistent and are located mainly between 60% and 80%. The most probable value of the optimal matched segments is about 20 bp for lower eukaryotes and 30 bp for higher eukaryotes. These results show that there are abundant functional units in the introns, and these functional units are correlated structurally with all kinds of sequences of mRNA. The interaction between the post-spliced introns and their corresponding mRNAs may play a key role in gene expression.

A novel approach to analyze the association characteristics between post-spliced introns and their corresponding mRNA.

Studies have shown that post-spliced introns promote cell survival when nutrients are scarce, and intron loss/gain can influence many stages of mRNA metabolism. However, few approaches are currently available to study the correlation between intron sequences and their corresponding mature mRNA sequences. Here, based on the results of the improved Smith-Waterman local alignment-based algorithm method (SW method) and binding free energy weighted local alignment algorithm method (BFE method), the optimal matched segments between introns and their corresponding mature mRNAs in Caenorhabditis elegans (C.elegans) and their relative matching frequency (RF) distributions were obtained. The results showed that although the distributions of relative matching frequencies on mRNAs obtained by the BFE method were similar to the SW method, the interaction intensity in 5'and 3'untranslated regions (UTRs) regions was weaker than the SW method. The RF distributions in the exon-exon junction regions were comparable, the effects of long and short introns on mRNA and on the five functional sites with BFE method were similar to the SW method. However, the interaction intensity in 5'and 3'UTR regions with BFE method was weaker than with SW method. Although the matching rate and length distribution shape of the optimal matched fragment were consistent with the SW method, an increase in length was observed. The matching rates and the length of the optimal matched fragments were mainly in the range of 60%-80% and 20-30bp, respectively. Although we found that there were still matching preferences in the 5'and 3'UTR regions of the mRNAs with BFE, the matching intensities were significantly lower than the matching intensities between introns and their corresponding mRNAs with SW method. Overall, our findings suggest that the interaction between introns and mRNAs results from synergism among different types of sequences during the evolutionary process.

Novel strategy of combined interstitial macrophage depletion with intravenous targeted therapy to ameliorate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease with poor prognosis and high mortality rate. In the process of IPF, inflammatory dysregulation of macrophages and massive fibroblast aggregation and proliferation destroy alveoli, which cause pulmonary dysfunction, and ultimately lead to death due to respiratory failure. In the treatment of IPF, crossing biological barriers and delivering drugs to lung interstitium are the major challenges. In order to avoid the side effect of macrophages proliferation, we proposed, designed, and evaluated the strategy which combined macrophage depletion by intervaginal space injection and intravenous targeted therapy on bleomycin mouse model. We found that it inhibited pulmonary macrophages, reduced macrophage depletion in non-target organs, improved pulmonary drug targeting, impeded the progression of pulmonary fibrosis, and accelerated the recovery of pulmonary function. This combination therapeutic strategy shows good biosafety and efficacy, induces a targeted response, and is promising as a practical new clinical approach towards the treatment of pulmonary fibrosis.

[Effect of Shugan Tiaoshen acupuncture combined with western medication on depression-insomnia comorbidity due to COVID-19 quarantine: a multi-central randomized controlled trial].

OBJECTIVE: To observe the effect of Shugan Tiaoshen acupuncture (acupuncture for soothing the liver and regulating the mentality) combined with western medication on depression and sleep quality in the patients with depression-insomnia comorbidity due to COVID-19 quarantine, and investigate the potential mechanism from the perspective of cortical excitability. METHODS: Sixty patients with depression-insomnia comorbidity due to COVID-19 quarantine were randomly divided into an acupuncture group and a sham-acupuncture group, 30 cases in each one. The patients of both groups were treated with oral administration of sertraline hydrochloride tablets. In the acupuncture group, Shugan Tiaoshen acupuncture was supplemented. Body acupuncture was applied to Yintang (GV 24+), Baihui (GV 20), Hegu (LI 4), Zhaohai (KI 6), Qihai (CV 6), etc. The intradermal needling was used at Xin (CO15), Gan (CO12) and Shen (CO10). In the sham-acupuncture group, the sham-acupuncture was given at the same points as the acupuncture group. The compensatory treatment was provided at the end of follow-up for the patients in the sham-acupuncture group. In both groups, the treatment was given once every two days, 3 times a week, for consecutive 8 weeks. The self-rating depression scale (SDS) and insomnia severity index (ISI) scores were compared between the two groups before and after treatment and 1 month after the end of treatment (follow-up) separately. The cortical excitability indexes (resting motor threshold [rMT], motor evoked potential amplitude [MEP-A], cortical resting period [CSP]) and the level of serum 5-hydroxytryptamine (5-HT) were measured before and after treatment in the two groups. RESULTS: After treatment and in follow-up, SDS and ISI scores were decreased in both groups compared with those before treatment (P<0.05), and the scores in the acupuncture group were lower than those in the sham-acupuncture group (P<0.05), and the decrease range in the acupuncture group after treatment was larger than that in the sham-acupuncture group (P<0.05). After treatment, rMT was reduced (P<0.05), while MEP-A and CSP were increased (P<0.05) in the acupuncture group compared with that before treatment. The levels of serum 5-HT in both groups were increased compared with those before treatment (P<0.05). The rMT in the acupuncture group was lower than that in the sham-acupuncture group, while MEP-A and CSP, as well as the level of serum 5-HT were higher in the acupuncture group in comparison with the sham-acupuncture group (P<0.05). CONCLUSION: Shugan Tiaoshen acupuncture combined with western medication can relieve depression and improve sleep quality in the patients with depression-insomnia comorbidity due to COVID-19 quarantine, which is probably related to rectifying the imbalanced excitatory and inhibitory neuronal functions.

Evolving deep convolutional neural networks by IP-based marine predator algorithm for COVID-19 diagnosis using chest CT scans.

This paper proposes an optimal structured deep convolutional neural network (DCNN) based on the marine predator algorithm (MPA) to construct a novel automatic diagnosis platform that may help radiologists identify COVID-19 and non-COVID-19 patients based on CT scan categorization and analysis. The goal is met with the help of three modifications based on the regular MPA. First, a novel encoding scheme based on Internet Protocol (IP) addresses is proposed, followed by introducing an Enfeebled layer to build a variable-length DCNN. Finally, the learning process divides big datasets into smaller chunks that are randomly evaluated. The proposed model is compared to the COVID-CT and SARS-CoV-2 datasets to undertake a complete evaluation. Following that, the performance of the developed model (DCNN-IPMPA) is compared to that of a typical DCNN and seven variable-length models using five well-known comparison metrics, as well as the receiver operating characteristic and precision-recall curves. The results show that the DCNN-IPMPA outperforms other benchmarks, with a final accuracy of 97.21% on the SARS-CoV-2 dataset and 97.94% on the COVID-CT dataset. Also, timing analysis indicates that the DCNN processing time is the best among all benchmarks as expected; however, DCNN-IPMPA represents a competitive result compared to the standard DCNN.