MSI-DTI: predicting drug-target interaction based on multi-source information and multi-head self-attention.

Identifying drug-target interactions (DTIs) holds significant importance in drug discovery and development, playing a crucial role in various areas such as virtual screening, drug repurposing and identification of potential drug side effects. However, existing methods commonly exploit only a single type of feature from drugs and targets, suffering from miscellaneous challenges such as high sparsity and cold-start problems. We propose a novel framework called MSI-DTI (Multi-Source Information-based Drug-Target Interaction Prediction) to enhance prediction performance, which obtains feature representations from different views by integrating biometric features and knowledge graph representations from multi-source information. Our approach involves constructing a Drug-Target Knowledge Graph (DTKG), obtaining multiple feature representations from diverse information sources for SMILES sequences and amino acid sequences, incorporating network features from DTKG and performing an effective multi-source information fusion. Subsequently, we employ a multi-head self-attention mechanism coupled with residual connections to capture higher-order interaction information between sparse features while preserving lower-order information. Experimental results on DTKG and two benchmark datasets demonstrate that our MSI-DTI outperforms several state-of-the-art DTIs prediction methods, yielding more accurate and robust predictions. The source codes and datasets are publicly accessible at https://github.com/KEAML-JLU/MSI-DTI.

Site-specific allylic C-H bond functionalization with a copper-bound N-centred radical.

Methods for selective C-H bond functionalization have provided chemists with versatile and powerful toolboxes for synthesis, such as the late-stage modification of a lead compound without the need for lengthy de novo synthesis1-5. Cleavage of an sp3 C-H bond via hydrogen atom transfer (HAT) is particularly useful, given the large number of available HAT acceptors and the diversity of reaction pathways available to the resulting radical intermediate6-17. Site-selectivity, however, remains a formidable challenge, especially among sp3 C-H bonds with comparable properties. If the intermediate radical could be further trapped enantioselectively, this should enable highly site- and enantioselective functionalization of C-H bonds. Here we report a copper (Cu)-catalysed site- and enantioselective allylic C-H cyanation of complex alkenes, in which a Cu(II)-bound nitrogen (N)-centred radical plays the key role in achieving precise site-specific HAT. This method is shown to be effective for a diverse collection of alkene-containing molecules, including sterically demanding structures and complex natural products and pharmaceuticals.

Copper-Catalyzed sp2 C-H Arylation and Alkynylation of Allenes via Hydrogen Atom Abstraction.

Development of methods for the sp2 C-H transformations of allenes has received much attention, and it presents a powerful tool for the synthesis of complicated allene-containing bioactive molecules. With a copper-catalyzed radical relay, sp2 allenic C-H arylation and alkynylation were established herein, using various aryl boronic acids and trimethoxysilyl-substituted alkynes as carbon nucleophiles and using electrophilic N-F reagents as nitrogen-centered radical precursors. These methods featured excellent site selectivity to deliver fully substituted allenes efficiently. Moreover, with silyl-substituted allenes as substrates, a subsequent dual sp2 C-H functionalization process was established as well, which allowed for the divergent synthesis of multifunctionalized allenes, significantly expanding their chemical spaces.

Palladium-Catalyzed Remote Hydrosulfonamidation of Alkenes: Access to Primary N-Alkyl Sulfamides by the SuFEx Reaction.

Herein, we establish a remote hydrosulfonamidation (HSA) of alkenes using palladium catalysis, where N-fluoro-N-(fluoro-sulfonyl)-carbamate with a sulfur(VI) fluoride moiety is demonstrated as a good amidation reagent. The anti-Markovnikov HSA reaction of terminal alkenes and the remote HSA of internal alkenes are achieved to efficiently yield primary N-alkyl-N-(fluorosulfonyl)-carbamates. In addition, this protocol enables the high-value utilization of alkane by combining the dehydrogenation process. The generated N-alkyl products exhibit a unique reactivity of sulfur(VI) fluorides, which can be directly transferred to N-alkyl sulfamides or amines via the sulfur(VI) fluoride exchange reaction, thereby streamlining their synthesis. Moreover, a (pyridyl) benzazole-type ligand proved to be vital for the excellent chemo- and regioselectivities.

Asymmetric 1,n-Remote Aminoacetoxylation of Unactivated Internal Alkenes Enabled by Palladium Catalysis.

A palladium-catalyzed asymmetric 1,n-remote aminoacetoxylation of cis-alkenes has been developed using PhI(OAc)2 as an oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine-oxazoline (Pyox) L3 with a tert-butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

Copper-Catalyzed Asymmetric Functionalization of Vinyl Radicals for the Access to Vinylarene Atropisomers.

A novel asymmetric radical strategy for the straightforward synthesis of atropisomerically chiral vinyl arenes has been established herein, proceeding through copper-catalyzed atroposelective cyanation/azidation of aryl-substituted vinyl radicals. Critical to the success of the radical relay process is the atroposelective capture of the highly reactive vinyl radicals with chiral L*Cu(II) cyanide or azide species. Moreover, these axially chiral vinylarene products can be easily transformed into atropisomerically enriched amides and amines, enantiomerically enriched benzyl nitriles via an axis-to-center chirality transfer process, and an atropisomerically pure organocatalyst for the chemo-, diastereo-, and enantioselective (4 + 2) cyclization reaction.

Site-Selective sp2 C-H Cyanation of Allenes via Copper-Catalyzed Radical Relay.

Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.

Serum Anion Gap Level Predicts All-Cause Mortality in Septic Patients: A Retrospective Study Based on the MIMIC III Database.

PURPOSE: Sepsis is a significant threat in the intensive care unit (ICU) worldwide because it has high morbidity and mortality rates. Early recognition and diagnosis of sepsis are essential for the prevention of adverse outcomes. The present study aimed to quantitatively assess the association between serum anion gap (AG) levels and 30- and 90-day all-cause mortality among sepsis patients. METHODS: Clinical data of patients diagnosed with sepsis were extracted from the Medical Information Mart for Intensive Care III (MIMIC III) database. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association between serum AG levels and all-cause mortality. A receiver operating characteristic (ROC) curve was drawn to quantify the efficacy of using the serum AG level to predict all-cause mortality. RESULTS: A total of 3811 patients were included in the study. The Kaplan-Meier curves showed that patients with higher serum AG levels had a shorter survival time than those with lower levels. Serum AG levels were found to be highly effective in predicting all-cause mortality secondary to sepsis (30-day: AUROC = 0.703; 90-day: AUROC = 0.696). The Cox regression model further indicated that the serum AG level was an independent risk factor for 30- and 90-day mortality in sepsis (HR 3.44, 95% CI 2.97-3.99 for 30-day; HR 3.17, 95% CI 2.76-3.65 for 90-day, P < 0.001 for both). CONCLUSIONS: High serum AG may be considered as an alternative parameter for predicting the death risk in sepsis when other variables are not immediately available. Prospective large-scale studies are needed to support its predictive value in the clinic.

Correlation of ABO blood groups with treatment response and efficacy in infants with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide.

OBJECTIVE: Not all infants with persistent pulmonary hypertension of the newborn (PPHN) respond to inhaled nitric oxide (iNO) therapy, as it is known to improve oxygenation in only 50% to 60% of cases. In this study, we investigated whether ABO blood groups were a relevant factor affecting the improvement of oxygenation by nitric oxide (NO) therapy in infants with PPHN. METHODS: This study was a retrospective, multicenter, and cohort-controlled trial that involved 37 medical units. Infants with PPHN who met the inclusion criteria and were treated with NO (a vasodilator) alone from July 1, 2015, to June 30, 2020, were selected and assigned into three groups: blood type A, blood type B, and blood type O (there were only 7 cases of blood type AB, with a small number of cases, and therefore, blood type AB was excluded for further analysis). The response to iNO therapy was defined as an increase in the ratio of the partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) > 20% from the basal value after treatment. Oxygenation was assessed mainly based on the two values, oxygenation index (OI) and PaO2/FiO2. The correlation of ABO blood groups with responses to iNO therapy and their influence on the efficacy of iNO therapy was analyzed based on the collected data. RESULTS: The highest proportion of infants with PPHN who eventually responded to iNO therapy was infants with blood type O. Infants with blood type O more readily responded to iNO therapy than infants with blood type B. Oxygenation after iNO treatment group was optimal in the blood type O group and was the worst in the blood type A group among the three groups. Infants with blood type O showed better efficacy than those with blood types A and B. CONCLUSION: ABO blood groups are correlated with responses to iNO therapy in infants with PPHN, and different blood groups also affect the efficacy of NO therapy in infants with PPHN. Specifically, infants with blood type O have a better response and experience the best efficacy to iNO therapy.

Copper-catalyzed radical relay in C(sp3)-H functionalization.

Radical-involved transition metal (TM) catalysis has greatly enabled new reactivities in recent decades. Copper-catalyzed radical relay offers enormous potential in C(sp3)-H functionalization which combines the unique regioselectivity of hydrogen atom transfer (HAT) and the versatility of copper-catalyzed cross-coupling. More importantly, significant progress has been achieved in asymmetric C-H functionalization through judicious ligand design. This tutorial review will highlight the recent advances in this rapidly growing area, and we hope this survey will inspire future strategic developments for selective C(sp3)-H functionalization.

Palladium-Catalyzed Remote Hydro-Oxygenation of Internal Alkenes: An Efficient Access to Primary Alcohols.

As a general method for the synthesis of alcohols, the direct oxygenation of alkenes is difficult to afford linear alcohols. Herein, we communicate the remote hydro-oxygenation of alkenes under palladium catalysis, in which both terminal and internal alkenes are suitable to yield the corresponding linear alcohols efficiently. A compatible SelectFluor/silane redox system plays an essential role for the excellent chemo- and regioselectivities. The reaction features a broad substrate scope and excellent functional group compatibility.

Enantioselective Radical Trifluoromethylation of Benzylic C-H Bonds via Cooperative Photoredox and Copper Catalysis.

The first enantioselective radical trifluoromethylation of benzylic C-H bonds has been established by a cooperative photoredox and copper catalysis system, providing straightforward access to structurally diverse benzylic trifluoromethylation products in good yields with excellent enantioselectivities under mild conditions. Our method features a broad substrate scope and excellent functional group compatibility. Merging the cooperative photoredox catalysis with copper catalysis is essential for the reaction, where the photoredox catalysis is used for the generation of benzylic radicals from alkyl arenes through a hydrogen atom transfer process and the copper catalysis is used for the enantioselective trifluoromethylation of the benzylic radicals.

Palladium(II)-Catalyzed Enantioselective Hydrooxygenation of Unactivated Terminal Alkenes.

A novel Pd(II)-catalyzed enantioselective Markovnikov hydrooxygenation of unactivated terminal alkenes using a substituted pyridinyl oxazoline (Pyox) ligand has been developed. Herein it was discovered that the (EtO)2MeSiH/BQ redox system is vital for the highly selective and efficient hydrooxygenation, where the alkylpalladium(II) species generated from enantioselective oxypalladation step is reduced by silane. This method provides efficient access to optically pure alcohol esters from easily available alkenes with excellent enantioselectivities and features a broad substrate scope.

Electrophotocatalytic Decoupled Radical Relay Enables Highly Efficient and Enantioselective Benzylic C-H Functionalization.

Asymmetric sp3 C-H functionalization has been demonstrated to substantially expedite target molecule synthesis, spanning from feedstocks upgradation to late-stage modification of complex molecules. Herein, we report a highly efficient and sustainable method for enantioselective benzylic C-H cyanation by merging electrophoto- and copper catalysis. A novel catalytic system allows one to independently regulate the hydrogen atom transfer step for benzylic radical formation and speciation of Cu(II)/Cu(I) to effectively capture the transient radical intermediate, through tuning the electronic property of anthraquinone-type photocatalyst and simply modulating the applied current, respectively. Such decoupled radical relay catalysis enables a unified approach for enantioselective benzylic C-H cyanation of diverse alkylarenes, many of which are much less reactive or even unreactive using the existing method relying on coupled radical relay. Moreover, the current protocol is also amenable to late-stage functionalization of bioactive molecules, including natural products and drugs.

MicroRNA-16-5p exacerbates sepsis by upregulating aerobic glycolysis via SIRT3-SDHA axis.

Sepsis is a life-threatening condition, and treatment for sepsis in clinic is often not available, partially due to insufficient understanding of the pathogenesis of sepsis. Extensive study to elucidate the pathogenesis is required to improve the clinical management and outcome of sepsis. In this study, we investigated the pathogenesis of sepsis using peripheral blood mononuclear cells (PBMCs) from septic patients and studied the underlying mechanism of miR-16-5p on aerobic glycolysis in lipopolysaccharide (LPS)-treated THP1 and Raw264.7 cells. The levels of RNA and protein were determined by real-time quantitative PCR and immunoblotting assay, respectively. The production of high mobility group box 1 (HMGB1) was measured by enzyme-linked immunosorbent assay. The levels of succinate and lactate were determined using colorimetric kits. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured by extracellular flux analyzer. The results showed that the expression of miR-16-5p was elevated, while sirtuin 3 (SIRT3) was decreased in PBMCs from septic patients and LPS-treated cells, along with accumulation of acetylated succinate dehydrogenase complex, subunit A. Concomitantly, an increase in HMGB1, succinate, lactate, as well as ECAR and a decrease in OCR were observed. Knockdown of miR-16-5p upregulated SIRT3 expression, facilitated SDHA deacetylation, and attenuated sepsis-related aerobic glycolysis. Further study identified that SIRT3 is targeted by miR-16-5p, and overexpression of SIRT3 rescued LPS-induced responses via deacetylation of SDHA. Our findings revealed a novel miR-16-5p-regulated SIRT3-SDHA axis in sepsis and provided novel insights for sepsis treatment.

Pseudoamaolides A-O, anti-inflammatory triterpene spiroketal lactones from seeds of Pseudolarix amabilis.

Fifteen new triterpenoids (1-15), along with twenty known ones (16-35), were isolated from Pseudolarix amabilis. The triterpenoid structures include multiple skeleton types, such as 2,3-seco-cycloartane, 3,4-seco-cycloartane, 3,4:9,10-diseco-cycloartane, and 3,4:8,9:9,10-triseco-cycloartane, as elucidated by extensive spectroscopy (1D NMR, 2D NMR, HRESIMS, and IR) and single-crystal X-ray diffraction. The anti-inflammatory activities of compounds 1-35 were evaluated. Compounds 3, 11, 16, 24, 25, and 26 suppressed the transcription of the NF-κB-dependent reporter gene in LPS-induced 293T/NF-κB-Luc cells with IC50 values of 0.12, 0.10, 0.30, 0.09, 0.49, and 0.35 µM, respectively. In addition, compound 16 showed anti-inflammatory activity against xylene-induced ear swelling in vivo with an inhibition rate of 44.7 % (30 mg/kg). Compound 16 significantly improved the disease activity index (DAI) of ulcerative colitis at a dose of 400 mg/kg in a dextran sodium sulfate (DSS)-induced mouse model of experimental ulcerative colitis (P < 0.01).

Two new diterpenoids from the stems of Rhododendron dauricum as GABAA receptor agonists.

Two new diterpenoids, dauricumins A (1) and B (2), together with two known aromatic meroterpenoids (3 and 4), were isolated from the petroleum ether soluble fraction of the stems from Rhododendron dauricum through an HPLC-MS-SPE-NMR combination strategy. The absolute configurations of 1 and 2 were elucidated by ECD calculations and [Rh2 (OCOCF3)4]-induced CD spectrum analysis. In a membrane potential FLIPR assay, confluentin (4) showed an agonistic effect on GABAA receptor (EC50 = 20 µM).

[Establishment of a system for regulating the gene expression of embryonic mouse cerebral cortex neural stem cells by in utero electroporation]. / å­å®«å† ç”µç©¿å­”æ³•è°ƒæŽ§é¼ èƒšå¤§è„‘çš®è´¨ç¥žç»å¹²ç»†èƒžåŸºå› è¡¨è¾¾ä½“ç³»çš„å»ºç«‹.

OBJECTIVES: To establish a system for regulating the gene expression of embryonic mouse cerebral cortex neural stem cells (NSCs) using in utero electroporation (IUE). METHODS: At embryonic day 14.5, the mouse cerebral cortex NSCs were electro-transfected with the pCIG plasmid injected into the ventricle of the mouse embryo. At embryonic day 16.5 or day 17.5, embryonic mouse brain tissues were collected to prepare frozen sections. Immunofluorescence staining was used to observe the proliferation, apoptosis, division, directional differentiation, migration, and maturation of NSCs. RESULTS: The differentiation of NSCs into intermediate progenitors, the proliferation and apoptosis of NSCs, and the morphological development of radial axis of radial glial cells were observed at embryonic day 16.5. The differentiation of NSCs into neurons in layers V-VI of the cerebral cortex, the migration of NSCs to the lateral cerebral cortex, the development of dendrites of migrating neurons, and the maturation of neurons were observed at embryonic day 17.5. CONCLUSIONS: The system for regulating the gene expression of embryonic mouse cerebral cortex NSCs can be established using IUE, which is useful for the study of neural development related to the proliferation, apoptosis, division, directional differentiation, migration and maturation of NSCs in the cerebral cortex.

Clinical treatment outcomes and their changes in extremely preterm twins: a multicenter retrospective study in Guangdong Province, China. / è¶ æœªæˆç†ŸåŒèƒŽå„¿ä¸´åºŠæ•‘æ²»ç»“å±€åŠå˜åŒ–åˆ†æžï¼šä¸€é¡¹å¹¿ä¸œçœå¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS: There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.

Enantioselective Copper-Catalyzed Radical Cyanation of Propargylic C-H Bonds: Easy Access to Chiral Allenyl Nitriles.

The first enantioselective copper-catalyzed cyanation of propargylic C-H bonds via radical relay was established using novel BoxOTMS ligands, providing an efficient and straightforward tool for the construction of structurally diverse chiral allenyl nitriles in good yields with excellent enantioselectivities. This reaction features high functional group tolerance and mild conditions. In addition, the chiral allene products can be readily converted to other chiral compounds via axis-to-center chirality transfer.