Multi-view contrastive heterogeneous graph attention network for lncRNA-disease association prediction.

MOTIVATION: Exploring the potential long noncoding RNA (lncRNA)-disease associations (LDAs) plays a critical role for understanding disease etiology and pathogenesis. Given the high cost of biological experiments, developing a computational method is a practical necessity to effectively accelerate experimental screening process of candidate LDAs. However, under the high sparsity of LDA dataset, many computational models hardly exploit enough knowledge to learn comprehensive patterns of node representations. Moreover, although the metapath-based GNN has been recently introduced into LDA prediction, it discards intermediate nodes along the meta-path and results in information loss. RESULTS: This paper presents a new multi-view contrastive heterogeneous graph attention network (GAT) for lncRNA-disease association prediction, MCHNLDA for brevity. Specifically, MCHNLDA firstly leverages rich biological data sources of lncRNA, gene and disease to construct two-view graphs, feature structural graph of feature schema view and lncRNA-gene-disease heterogeneous graph of network topology view. Then, we design a cross-contrastive learning task to collaboratively guide graph embeddings of the two views without relying on any labels. In this way, we can pull closer the nodes of similar features and network topology, and push other nodes away. Furthermore, we propose a heterogeneous contextual GAT, where long short-term memory network is incorporated into attention mechanism to effectively capture sequential structure information along the meta-path. Extensive experimental comparisons against several state-of-the-art methods show the effectiveness of proposed framework.The code and data of proposed framework is freely available at https://github.com/zhaoxs686/MCHNLDA.

Enantioselective [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with Vinylazaarenes through Asymmetric Photoredox Catalysis.

Here we present a highly enantioselective [2π + 2σ] photocycloaddition of bicyclo[1.1.0]butanes (BCBs). The reaction uses a variety of vinylazaarenes as partners and is catalyzed by a polycyclic aromatic hydrocarbon (PAH)-containing chiral phosphoric acid as a bifunctional chiral photosensitizer. A wide array of pharmaceutically important bicyclo[2.1.1]hexane (BCH) derivatives have been synthesized with high yields, enantioselectivity, and diastereoselectivity. In addition to the diverse 1-ketocarbonyl-3-substituted BCBs, α/ß-substituted vinylazaarenes are compatible with such an unprecedented photoredox catalytic pathway, resulting in the successful assembly of an all-carbon quaternary stereocenter or two adjacent tertiary stereocenters on the product.

Heterogeneous graph attention network based on meta-paths for lncRNA-disease association prediction.

MOTIVATION: Discovering long noncoding RNA (lncRNA)-disease associations is a fundamental and critical part in understanding disease etiology and pathogenesis. However, only a few lncRNA-disease associations have been identified because of the time-consuming and expensive biological experiments. As a result, an efficient computational method is of great importance and urgently needed for identifying potential lncRNA-disease associations. With the ability of exploiting node features and relationships in network, graph-based learning models have been commonly utilized by these biomolecular association predictions. However, the capability of these methods in comprehensively fusing node features, heterogeneous topological structures and semantic information is distant from optimal or even satisfactory. Moreover, there are still limitations in modeling complex associations between lncRNAs and diseases. RESULTS: In this paper, we develop a novel heterogeneous graph attention network framework based on meta-paths for predicting lncRNA-disease associations, denoted as HGATLDA. At first, we conduct a heterogeneous network by incorporating lncRNA and disease feature structural graphs, and lncRNA-disease topological structural graph. Then, for the heterogeneous graph, we conduct multiple metapath-based subgraphs and then utilize graph attention network to learn node embeddings from neighbors of these homogeneous and heterogeneous subgraphs. Next, we implement attention mechanism to adaptively assign weights to multiple metapath-based subgraphs and get more semantic information. In addition, we combine neural inductive matrix completion to reconstruct lncRNA-disease associations, which is applied for capturing complicated associations between lncRNAs and diseases. Moreover, we incorporate cost-sensitive neural network into the loss function to tackle the commonly imbalance problem in lncRNA-disease association prediction. Finally, extensive experimental results demonstrate the effectiveness of our proposed framework.

Palladium-Catalyzed Carbonylation Reaction of Indole/Pyrrole Involving HCFO-1233zd (E).

3-Indole-3-one is a key intermediate in the synthesis of many drugs and plays an important role in synthetic chemistry and biochemistry. A new method for synthesizing trifluoromethylated 3-indoleketones by Pd(0)-catalyzed carbonylation was introduced. In the absence of additives, 1-chloro-3,3,3-trifluoropropyl (an inexpensive and environmentally friendly synthetic block of trifluoromethyl) reacts with indole and carbon monoxide to generate trifluoromethylindole ketones with good yields, regioselectivity, and chemical selectivity; furthermore, the products exhibit strong resistance to basic functional groups, such as alkynes, aldehydes, and esters. In addition to the conversion of indole compounds into corresponding products, pyrrole and heteroindole may be suitable for corresponding chemical transformations. This study provides a synthetic method for the further construction of trifluoromethylated 3-indole ketones.

Visible-Light-Induced Regioselective Cascade Radical Cyclization of α-Bromocarbonyls: Access to Benzazepine Derivatives.

Visible-light-induced regioselective cascade radical cyclization of α-bromocarbonyls for the synthesis of benzazepine derivatives is described. In the presence of fac-Ir(ppy)3 (2.0 mol %) as a photocatalyst, 2,6-lutidine as a base, and dichloromethane as a solvent, the reactions proceed smoothly to afford seven-membered rings in good yields. This protocol features a broad substrate scope, excellent functional group tolerance, and mild reaction conditions. Preliminary mechanistic studies reveal that the generation of the α-carbon radical is more prone to react with the 1,1-diphenylethylene tethered acrylamide to generate the stable seven-membered heterocycle.

Improving Measurement Accuracy of Deep Hole Measurement Instruments through Perspective Transformation.

Deep hole measurement is a crucial step in both deep hole machining and deep hole maintenance. Single-camera vision presents promising prospects in deep hole measurement due to its simple structure and low-cost advantages. However, the measurement error caused by the heating of the imaging sensor makes it difficult to achieve the ideal measurement accuracy. To compensate for measurement errors induced by imaging sensor heating, this study proposes an error compensation method for laser and vision-based deep hole measurement instruments. This method predicts the pixel displacement of the entire field of view using the pixel displacement of fixed targets within the camera's field of view and compensates for measurement errors through a perspective transformation. Theoretical analysis indicates that the perspective projection matrix changes due to the heating of the imaging sensor, which causes the thermally induced measurement error of the camera. By analyzing the displacement of the fixed target point, it is possible to monitor changes in the perspective projection matrix and thus compensate for camera measurement errors. In compensation experiments, using target displacement effectively predicts pixel drift in the pixel coordinate system. After compensation, the pixel error was suppressed from 1.99 pixels to 0.393 pixels. Repetitive measurement tests of the deep hole measurement instrument validate the practicality and reliability of compensating for thermal-induced errors using perspective transformation.

Catalytic Asymmetric Redox-Neutral [3+2] Photocycloadditions of Cyclopropyl Ketones with Vinylazaarenes Enabled by Consecutive Photoinduced Electron Transfer.

Consecutive photoinduced electron transfer (ConPET) is a powerful and atom-economical protocol to overcome the limitations of the intrinsic redox potential of visible light-absorbing photosensitizers, thereby considerably improving the substrate and reaction types. Likely because such an exothermic single-electron transfer (SET) process usually does not require the aid of chiral catalysts, resulting in an inevitable racemic background reaction, notably, no enantioselective manifolds have been reported. Herein, we report on the viability of cooperative ConPET and chiral hydrogen-bonding catalysis for the [3+2] photocycloaddition of cyclopropyl ketones with vinylazaarenes. In addition to enabling the first use of olefins that preferentially interact with chiral catalysts, this catalysis platform paves the way for the efficient synthesis of pharmaceutically and synthetically important cyclopentyl ketones functionalized by azaarenes with high yields, ees and dr. The robust capacity of the method can be further highlighted by the low loading of the chiral catalyst (1.0 mol %), the good compatibility of both 2-azaarene and 3-pyridine-based olefins, and the successful concurrent construction of three stereocenters on cyclopentane rings involving an elusive but important all-carbon quaternary.

Enantioselective Chemodivergent Three-Component Radical Tandem Reactions through Asymmetric Photoredox Catalysis.

Chemodivergent synthesis has been achieved in asymmetric photocatalysis. Under a dual catalyst system consisting of a chiral phosphoric acid and DPZ as a photosensitizer, different inorganic bases enabled the formation of two sets of valuable products from the three-component radical tandem transformations of 2-bromo-1-arylenthan-1-ones, styrenes, and quinoxalin-2(1H)-ones. The key to success was the distinct pKa environment, in which the radicals that formed on the quinoxalin-2(1H)-one rings after two radical addition processes underwent either single-electron oxidation or single-electron reduction. In addition, this work represents the first use of quinoxalin-2(1H)-ones in asymmetric photoredox catalysis.

Asymmetric Olefin Isomerization via Photoredox Catalytic Hydrogen Atom Transfer and Enantioselective Protonation.

Asymmetric olefin isomerization can be appreciated as an ideal synthetic approach to access valuable enantioenriched C═C-containing molecules due to the excellent atom economy. Nonetheless, its occurrence usually requires a thermodynamic advantage, namely, a higher stability of the product to the substrate. It has thus led to rather limited examples of success. Herein, we report a photoredox catalytic hydrogen atom transfer (HAT) and enantioselective protonation strategy for the challenging asymmetric olefin isomerization. As a paradigm, by establishing a dual catalyst system involving a visible light photosensitizer DPZ and a chiral phosphoric acid, with the assistance of N-hydroxyimide to perform HAT, a wide array of allylic azaarene derivatives, featuring α-tertiary carbon stereocenters and ß-C═C bonds, was synthesized with high yields, ees, and E/Z ratios starting from the conjugated α-substituted alkenylazaarene E/Z-mixtures. The good compatibility of assembling deuterium on stereocenters by using inexpensive D2O as a deuterium source further underscores the broad applicability and promising utility of this strategy. Moreover, mechanistic studies have provided clear insights into its challenges in terms of reactivity and enantioselectivity. The exploration will robustly inspire the development of thermodynamically unfavorable asymmetric olefin isomerizations.

Metal-Free Construction of Multisubstituted Indolizines via Intramolecular Amination of Allylic Alcohols.

An intramolecular amination of allylic alcohols is developed as an efficient and general access to biologically important multisubstituted indolizines and their variants. Two metal-free synthetic platforms including using aqueous hydrochloric acid solution as the solvent and p-toluenesulfonic acid as the catalyst have been established, enabling the divergent synthesis of these valuable compounds in high yields.

NHC-Catalyzed Tandem Reaction: A Strategy for the Synthesis of 2-Pyrrolidinone-Functionalized Phenanthridines.

Herein, an N-heterocyclic carbene (NHC)-catalyzed tandem cyclization/addition/cyclization reaction of 2-isocyanobiaryls and α-bromo-N-cinnamylamides for the synthesis of 2-pyrrolidinone-functionalized phenanthridines is developed. This protocol features a radical cascade process, broad substrate scope, and good functional group compatibility under metal- and oxidant-free reaction conditions.

LysP53 activity against Salmonella and its application in decontamination of Salmonella on fresh romaine lettuce.

Salmonella is a zoonotic pathogen that is commonly associated with foodborne disease outbreaks. This study found that a newly identified Gram-negative lysin LysP53 had good activity against a wide range of Salmonella, including Salmonella Newington, Salmonella Typhimurium, and Salmonella Dublin. Without the help of an outer membrane permeabilizer, 4 µM LysP53 could reduce 97.6% of planktonic Salmonella Enteritidis and 90% of the bacteria in biofilms. Moreover, LysP53 was highly thermostable because it maintained >90% activity even after exposure to temperatures up to 95 °C. Although high concentrations of salts could reduce the activity, LysP53 was found safe for oral gavage of mice without affecting body weights and cytokines in sera and able to reduce 90% of Salmonella Enteritidis loads on fresh romaine lettuce after 30 min of treatment. Because of its good activity against a wide range of bacteria, thermal stability, safe for oral administration, LysP53 could be used as a biocontrol agent for reducing bacterial loads in fresh vegetable food. KEY POINTS: • Lysin LysP53 has high bactericidal activity against Salmonella. • LysP53 is thermostable even at high temperature of up to 95 °C. • LysP53 can be used for topical decontamination of Salmonella on vegetables.

Transcriptome analysis of differentially expressed genes involved in the inflammageing status of gingiva in aged mice.

OBJECTIVE: To identify immune-inflammation-related genes related to susceptibility to periodontitis in the gingiva of aged mice with RNA sequencing. METHODS: Gingival samples from 18-month-old, 8-week-old healthy mice and 8-week-old mice with periodontitis were taken for RNA-seq. The differentially expressed genes (DEGs) were validated with qRT-PCR using mouse and human gingival samples. RESULTS: 977 (upregulated) and 1824 (downregulated) genes were identified in the old compared with the young mice. 14.2% were related to immune-inflammatory responses. This proportion of overlap (ageing and periodontitis)-DEGs was higher (48.4%). Enrichment analysis of overlap (ageing and periodontitis)-DEGs showed that the top five GO and KEGG terms were related to the immune-inflammatory responses, and disease analysis was more specific to periodontitis. The candidate genes of overlap (ageing and periodontitis)-DEGs selected by protein-protein interaction (PPI) network showed the higher match with clinical data sets. By qRT-PCR, nine candidate genes were identified as hub genes that are associated with susceptibility to periodontitis in the elderly, including CXCL3, CXCL5, CSF3, CSF3R, FPR1, IL1B, OSM, SERPINE1 and SELP. CONCLUSION: Our studies provide insights into the mechanisms by which ageing affects the immune-inflammatory status of gingival tissues, thereby increasing the risk of periodontitis. It may become targets for future prevention of periodontitis.

Kinetic Resolution of Azaarylethynyl Tertiary Alcohols by Chiral Brønsted Acid Catalysed Phosphine-Mediated Deoxygenation.

A chiral Brønsted acid catalysed phosphine-mediated deoxygenation protocol is reported. This metal-free method provides a precise kinetic resolution platform for azaarylethynyl tertiary alcohols, which are a broad category of biologically and synthetically important azaarene derivatives. In addition to providing an efficient method for the first asymmetric preparation of these tertiary alcohols, the strategy facilitates the construction of azaaryl-functionalized allenes with good to excellent enantioselectivities. The high selectivity factors (s up to 235), broad substrate scope, and ability to convert azaaryl compounds into both chiral tertiary alcohols and allenes robustly underscore the efficiency and promising utility of this method. The practicability is further validated by the successful synthesis of deuterated allenes with high ee values and substantial incorporation of deuterium using inexpensive D2 O as the deuterium source.

Catalytic Asymmetric Hydrophosphinylation of 2-Vinylazaarenes to Access P-Chiral 2-Azaaryl-Ethylphosphine Oxides.

A chiral Brønsted acid-catalysed asymmetric hydrophosphinylation of 2-vinylazaarenes by secondary phosphine oxides is described. A variety of P-chiral 2-azaaryl-ethylphosphine oxides are synthesized with high yields and ees, of which both the substituents of phosphines and azaarenes can be flexibly modulated, underscoring an exceptionally broad scope of substrates. These adducts are valuable to asymmetric metal catalysis since the resultant P-chiral tertiary phosphines from the reduction of them are verified as a kind of effective C1 -symmetric chiral 1,5-hybrid P,N-ligands. Importantly, this catalysis platform enables the generic and efficient kinetic resolution of P-chiral secondary phosphine oxides. It thus provides an expedient approach to access the enantiomers of the P-chiral tertiary phosphine oxides derived from asymmetric hydrophosphinylation, further improving the utility of the method.

Catalytic Asymmetric Reductive Azaarylation of Olefins via Enantioselective Radical Coupling.

Visible-light-driven photocatalytic reductive azaarylation has been widely used to construct the important imine-containing azaarene derivatives. In addition to the direct use of various commercially available cyanoazaarenes as feedstocks, the synthetic advantages include precise regioselectivity, high efficiency, mild reaction conditions, and good functional group tolerance. However, although many efficient reductive azaarylation methods have been established, the example of an enantioselective manner is still unmet, which most likely can be ascribed to the highly reactive radical coupling as the key step of forming stereocenters. Exploring the feasibility of enantiocontrol thus constitutes an attractive but highly challenging task. Here, we demonstrate that chiral hydrogen-bonding/photosensitizer catalysis is a viable platform as it enables the realization of the first enantioselective manifold. A variety of acyclic and cyclic enones as the reaction partners are compatible with the dual catalyst system, leading to a wide array of valuable enantioenriched azaarene variants with high yields and ees. Regulating the types of chiral catalysts represents one of the important manners to success, in which several readily accessible Cinchona alkaloid-derived bifunctional catalysts are introduced in asymmetric photochemical reactions.

Influence of lower-limb mechanical axis on the curative effect of medial high tibial osteotomy for knee osteoarthritis.

PURPOSE: To investigate the effect of the ratio of the medial tibial plateau width to the total tibial plateau width on the therapeutic efficacy of high tibial osteotomy (HTO) on the medial side for the treatment of knee osteoarthritis. METHODS: In this study, we retrospectively analyzed information of 278 patients who underwent medial HTO for knee osteoarthritis with varus deformity. The Tinetti Gait and Balance Assessment Tool, the Visual Analog Scale (VAS), and the Knee Society Scoring System (KSS) were used to comprehensively evaluate the function of the knee joint after HTO. RESULTS: After adjusting for potential confounding factors (i.e., age, gender, body mass index/BMI, and surgical site), the Tinetti assessment score was optimized when the degree of correction was 53.67%, with the ß-value on the left and right sides of the inflection point of 0.49 (confidence interval, CI: 0.20, 0.78, P = 0.0009) and- 0.26 (95% CI: - 0.30, - 0.22, P < 0.0001), respectively. The KSS score was optimized when the degree of correction was 55.45%, with the ß-value on the left and right sides of the inflection point of 2.77 (95% CI: 1.64, 3.90, P < 0.0001) and - 1.18 (95% CI: - 1.46, - 0.91, P < 0.0001), respectively. The VAS score was the lowest when the degree of correction was 55.00%, with the ß-value on the left and right sides of the inflection point of - 0.16 (95% CI: - 0.29, - 0.03, P = 0.0146) and 0.08 (95% CI: 0.05, 0.10, P < 0.0001), respectively. Stratified analysis showed that the BMI affected the Tinetti assessment score (ß = - 0.14, 95% CI: - 0.24, - 0.04, P = 0.0071). According to the smooth-curve fitting results, when the BMI was > 28, the Tinetti assessment score showed a negative trend. CONCLUSION: The degree of lower-limb mechanical axis correction correlated with the functional status of the knee joint after MOW HTO. When the ratio of the medial tibial plateau width to the total tibial plateau width was approximately 55%, the post-MOW HTO outcomes were optimized and the patients experienced the highest satisfaction. In addition, very high BMI was not conducive for the postoperative recovery of the knee joint function. LEVEL OF EVIDENCE: III Case-control study/Retrospective comparative study.

Selenocystine-Derived Label-Free Fluorescent Schiff Base Nanocomplex for siRNA Delivery Synergistically Kills Cancer Cells.

Chemo and siRNA synergic treatments for tumors is a promising new therapeutic trend. Selenocystine, a selenium analog of cysteine, has been considered a potential antitumor agent due to its redox perturbing role. In this study, we developed a nanocarrier for siRNA based on a selenocystine analog engineered polyetherimide and achieved traceable siRNA delivery and the synergic killing of tumor cells. Notably, we applied the label-free Schiff base fluorescence mechanism, which enabled us to trace the siRNA delivery and to monitor the selenocystine analogs' local performance. A novel selenocystine-derived fluorescent Schiff base linker was used to crosslink the polyetherimide, thereby generating a traceable siRNA delivery vehicle with green fluorescence. Moreover, we found that this compound induced tumor cells to undergo senescence. Together with the delivery of a siRNA targeting the anti-apoptotic BCL-xl/w genes in senescent cells, it achieved a synergistic inhibition function by inducing both senescence and apoptosis of tumor cells. Therefore, this study provides insights into the development of label-free probes, prodrugs, and materials towards the synergic strategies for cancer therapy.

A Structured Skin Care Protocol for Preventing and Treating Incontinence-associated Dermatitis in Critically Ill Patients.

OBJECTIVE: To examine the effectiveness of a structured skin care protocol for preventing and treating incontinence-associated dermatitis (IAD) in critically ill patients. METHODS: Participants were drawn from the ICUs of three teaching hospitals between January 2016 and December 2017. Patients were eligible if they were ≥18 years old, had idiopathic fecal incontinence, had diarrhea but were unable to sense it, and were expected to stay in the ICU for at least 72 hours after developing incontinence. A total of 143 patients were enrolled: 79 in the experimental group and 64 in the control group. In the first phase of the study, routine skin care measures were used; in the second phase, three ICU caregivers were trained to provide a structured skin care protocol. Trained research team members conducted the data collection and analysis. The TREND (Transparent Reporting of Evaluations with Nonrandomized Designs) Statement Checklist was followed in reporting the study results. RESULTS: Application of the structured skin care protocol reduced the incidence of IAD from 35.9% in the control phase to 17.7% in the intervention phase (χ2 = 6.117, P < .05) and also decreased the severity of IAD (z = -2.023, P < .05). Further, IAD developed later (z = -2.116, P < .05) in the intervention group than in the control group. In addition, the nursing times to prevent or manage IAD did not differ significantly between the groups (t = -0.258, P > .05; t = -1.190, P > .05). CONCLUSIONS: Use of the developed structured skin care protocol for IAD in critically ill patients lowered the incidence and severity of IAD and delayed IAD development.