Visible-Light-Driven Iron-Catalyzed 1,2-Difluoroalkylthiolation of Alkenes.

The synthesis of medicinally interesting aryldifluoromethylated compounds has drawn significant research attention in recent years. Herein, we report an unprecedented iron-mediated process for the selective defluorination of trifluoromethylarenes to achieve the 1,2-difluoroalkylthiolation of alkenes. Preliminary mechanistic studies revealed that thiolate anion, trifluoromethylarene, and iron cation could form an electron donor-acceptor (EDA) complex, which induced selective defluorination and then difunctionalization of alkenes to obtain aryldifluoromethylated products. The generated aryldifluoromethylated compounds make it difficult to form an EDA complex again, thus avoiding excessive defluorination. This conversion has concise and ambient reaction conditions and provides an alternative solution for obtaining difluorobenzylic intermediates.

Design of Selective PARP-1 Inhibitors and Antitumor Studies.

Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.

Perceptually Inspired C0-Continuity Haptic Shape Display with Trichamber Soft Actuators.

Shape display devices composed of actuation pixels enable dynamic rendering of surface morphological features, which have important roles in virtual reality and metaverse applications. The traditional pin-array solution produces sidestep-like structures between neighboring pins and normally relies on high-density pins to obtain curved surfaces. It remains a challenge to achieve continuous curved surfaces using a small number of actuated units. To address the challenge, we resort to the concept of surface continuity in computational geometry and develop a C0-continuity shape display device with trichamber fiber-reinforced soft actuators. Each trichamber unit produces three-dimensional (3D) deformation consisting of elongation, pitch, and yaw rotation, thus ensuring rendered surface continuity using low-resolution actuation units. Inspired by human tactile discrimination threshold on height and angle gradients between adjacent units, we proposed the mathematical criteria of C0-continuity shape display and compared the maximal number of distinguishable shapes using the proposed device in comparison with typical pin-array. We then established a shape control model considering the nonlinearity of soft materials to characterize and control the soft device to display C0-continuity shapes. Experimental results showed that the proposed device with nine trichamber units could render typical sets of distinguishable C0-continuity shape sequence changes. We envision that the concept of C0-continuity shape display with 3D deformation capability could improve the fidelity of the rendered shapes in many metaverse scenarios such as touching human organs in medical palpation simulations.

The road less taken: Dihydroflavonol 4-reductase inactivation and delphinidin anthocyanin loss underpins a natural intraspecific flower colour variation.

Visual cues are of critical importance for the attraction of animal pollinators, however, little is known about the molecular mechanisms underpinning intraspecific floral colour variation. Here, we combined comparative spectral analysis, targeted metabolite profiling, multi-tissue transcriptomics, differential gene expression, sequence analysis and functional analysis to investigate a bee-pollinated orchid species, Glossodia major with common purple- and infrequent white-flowered morphs. We found uncommon and previously unreported delphinidin-based anthocyanins responsible for the conspicuous and pollinator-perceivable colour of the purple morph and three genetic changes underpinning the loss of colour in the white morph - (1) a loss-of-function (LOF; frameshift) mutation affecting dihydroflavonol 4-reductase (DFR1) coding sequence due to a unique 4-bp insertion, (2) specific downregulation of functional DFR1 expression and (3) the unexpected discovery of chimeric Gypsy transposable element (TE)-gene (DFR) transcripts with potential consequences to the genomic stability and post-transcriptional or epigenetic regulation of DFR. This is one of few known cases where regulatory changes and LOF mutation in an anthocyanin structural gene, rather than transcription factors, are important. Furthermore, if TEs prove to be a frequent source of mutation, the interplay between environmental stress-induced TE evolution and pollinator-mediated selection for adaptive colour variation may be an overlooked mechanism maintaining floral colour polymorphism in nature.

Radical Addition-Enabled C-C σ-Bond Cleavage/Reconstruction to Access Functional Indanones: Total Synthesis of Carexane L.

C-C σ-bond cleavage and reconstruction is a significant tool for structural modification in synthetic chemistry but it remains a formidable challenge to perform on unstrained skeletons. Herein, we describe a radical addition-enabled C-C σ-bond cleavage/reconstruction reaction of unstrained allyl ketones to access various functional indanones bearing a benzylic quaternary center. The synthetic utility of this method has been showcased by the first total synthesis of carexane L, an indanone-based natural product.

Probiotics Pediococcus acidilactici GR-1 promotes the functional strains and remodels gut microbiota to reduce the Cr(VI) toxicity in a dual-chamber simulated intestinal system.

Numerous animal studies have demonstrated the toxicity of hexavalent chromium [Cr(VI)] and the bioremediative effects of probiotics on the composition and functions of gut microbiota. Since the precise mechanisms of Cr(VI) detoxification and its interactions with human gut microbiota were unknown, a novel dual-chamber simulated intestinal (DCSI) system was developed to maintain both the stability of the simulated system and the composition of the gut microbiota. Probiotic GR-1 was found to regulate intestinal gut microbiota, thereby reducing the toxicity of Cr(VI) within the DCSI system. The results indicate that Cr(VI) levels were reduced from 2.260 ± 0.2438 µg/g to 1.7086 ± 0.1950 µg/g in the gut microbiota cell pellet, and Cr(VI) permeability decreased from 0.5521 ± 0.1132 µg/L to 0.3681 ± 0.0178 µg/L after 48 h in simulated gut fluid. Additionally, the removal rate of 1,1-Diphenyl-2-picrylhydrazyl (DPPH), reducibility (Vitamin C), and total antioxidant capacity (T-AOC) increased by 50.83%, 31.70%, and 27.56%, respectively, following probiotic treatment. The increase in antioxidant capacity correlated with total Cr removal (P < 0.05, r from -0.80 to 0.73). 16S rRNA sequencing analysis showed that gut microbiota composition was reshaped by the addition of probiotics, which regulated the recovery of the functional gut microbiota to normal levels, rather than restoring the entire gut microbiota composition for community function. Thus, this study not only demonstrates the feasibility and stability of culturing gut microbiota but also offers a new biotechnological approach to synthesizing functional communities with functional strains for environmental risk management.

Effect of Manganese on the Strength-Toughness Relationship of Low-Carbon Copper and Nickel-Containing Hull Steel.

The influence of varying the manganese (Mn) contents of high-strength copper-containing hull steel on its microstructural evolution and mechanical properties was investigated. With increasing Mn content from 2 to 5%, the tensile strength of the steel increased by ~100 MPa, while the elongation of steel remained at ~23.5%, indicating good plasticity. However, the 2Mn sample had 128 J higher low-temperature (-84 °C) impact work than the 5Mn sample. The microstructures of different Mn steels were composed of fresh martensite (FM), ferrite/tempered martensite (F/TM), and reversed austenite (RA). The increase in Mn content markedly increased the presence of RA and intensified the work hardening caused by the transformation-induced plasticity (TRIP) effect during the tensile process. However, as the phase transformation in different Mn steels occurred in the early stage of strain and did not extend throughout the entire plastic deformation process, increasing plasticity via phase transformation was difficult. In addition, although the volume fraction of RA increased significantly in 4Mn and 5Mn steels, the stability of RA significantly decreased. The presence of numerous metastable blocks and coarse lath-like RA contributed little to low-temperature impact work and was even detrimental to toughness. The substantial fresh martensite resulting from phase transformation facilitated microcrack generation, owing to rapid volume expansion and mutual impacts, thus reducing the work required for crack formation. Additionally, the abundance of deformation twins significantly reduced the work needed for crack propagation. These combined actions significantly reduced the low-temperature toughness of 4Mn and 5Mn steels.

DNA-Binding with One Finger (Dof) Transcription Factor Gene Family Study Reveals Differential Stress-Responsive Transcription Factors in Contrasting Drought Tolerance Potato Species.

DNA-binding with one finger (Dof) proteins comprise a large family that play central roles in stress tolerance by regulating the expression of stress-responsive genes via the DOFCORE element or by interacting with other regulatory proteins. Although the Dof TF has been identified in a variety of species, its systemic analysis in potato (Solanum tuberosum L.) is lacking and its potential role in abiotic stress responses remains unclear. A total of 36 potential Dof genes in potato were examined at the genomic and transcriptomic levels in this work. Five phylogenetic groups can be formed from these 36 Dof proteins. An analysis of cis-acting elements revealed the potential roles of Dofs in potato development, including under numerous abiotic stress conditions. The cycling Dof factors (CDFs) might be the initial step in the abiotic stress response signaling cascade. In potato, five CDFs (StCDF1/StDof19, StCDF2/StDof4, StCDF3/StDof11, StCDF4/StDof24, and StCDF5/StDof15) were identified, which are homologs of Arabidopsis CDFs. The results revealed that these genes were engaged in a variety of abiotic reactions. Moreover, an expression analysis of StDof genes in two potato cultivars ('Long10' (drought tolerant) and 'DXY' (drought susceptible)) of contrasting tolerances under drought stress was carried out. Further, a regulatory network mediated by lncRNA and its target Dofs was established. The present study provides fundamental knowledge for further investigation of the roles of Dofs in the adaptation of potato to drought stress, aiming to provide insights into a viable strategy for crop improvement and stress-resistance breeding.

Evaluating the mode of action of perfluorooctanoic acid-induced liver tumors in male Sprague-Dawley rats using a toxicogenomic approach.

The mode of action (MOA) underlying perfluorooctanoic acid (PFOA)-induced liver tumors in rats is proposed to involve peroxisome proliferator-activated receptor α (PPARα) agonism. Despite clear PPARα activation evidence in rodent livers, the mechanisms driving cell growth remain elusive. Herein, we used dose-responsive apical endpoints and transcriptomic data to examine the proposed MOA. Male Sprague-Dawley rats were treated with 0, 1, 5, and 15 mg/kg PFOA for 7, 14, and 28 days via oral gavage. We showed PFOA induced hepatomegaly along with hepatocellular hypertrophy in rats. PPARα was activated in a dose-dependent manner. Toxicogenomic analysis revealed six early biomarkers (Cyp4a1, Nr1d1, Acot1, Acot2, Ehhadh, and Vnn1) in response to PPARα activation. A transient rise in hepatocellular DNA synthesis was demonstrated while Ki-67 labeling index showed no change. Transcriptomic analysis indicated no significant enrichment in pathways related to DNA synthesis, apoptosis, or the cell cycle. Key cyclins including Ccnd1, Ccnb1, Ccna2, and Ccne2 were dose-dependently suppressed by PFOA. Oxidative stress and the nuclear factor-κB signaling pathway were unaffected. Overall, evidence for PFOA-induced hepatocellular proliferation was transient within the studied timeframe. Our findings underscore the importance of considering inter-species differences and chemical-specific effects when evaluating the carcinogenic risk of PFOA in humans.

Small Molecule SHP2 Inhibitor LXQ-217 Affects Lung Cancer Cell Proliferation in Vitro and in Vivo.

BACKGROUND: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors. METHODS: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217. RESULTS: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs. CONCLUSIONS: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.

Damping Properties of Selective Laser-Melted Medium Manganese Mn-xCu Alloy.

In this work, selective laser melting (SLM) technology was applied to directly realize the in situ synthesis of medium manganese Mn-xCu (x = 30-40 wt.%) alloys based on the blended elemental powders. The effects of heat treatment on the microstructural evolution and damping properties of the SLMed Mn-xCu alloys were investigated. The metastable miscibility gap was studied by thermodynamic modeling and microhardness measurement. The results showed that γ-(Mn, Cu) phase with dendritic arm spacing (DAS) of 0.9-1.2 µm was the main constituent phase in the as-SLMed alloys, which was one to two orders of magnitude finer than those of the as-cast samples. Aging at 400-480°C for the Mn-30%Cu or 430°C for Mn-40%Cu alloys can induce spinodal decomposition, martensitic transformation, and α-phase precipitation, whose direct evidence was provided for the first time by transmission electron microscopy and 3D atom probe tomography in the work. The miscibility gap obtained from thermodynamics calculation was basically consistent with the microhardness results for the SLMed Mn-xCu alloys. Solution and aging (SA) treatment can improve the microstructure, tensile and damping properties of the SLMed Mn-xCu alloys more obviously than aging treatment. A 2.3-2.8 and 4.3-4.5 times increase was produced in damping capacity in the aged SLMed and SLMed+SAed Mn-xCu samples, respectively.

Rab3a attenuates spinal cord injury by mediating vesicle release.

BACKGROUND: Rab3a regulates vesicle secretion and transport. Emerging evidences have shown that extracellular vesicles (EVs) can reach target lesions of injured spinal cords and exert a positive effect on these lesions. However, the molecular mechanism by which Rab3a regulates vesicle secretion to ameliorate spinal cord injury (SCI) is not fully understood. METHODS: An SCI rat model was established which was used to examine the pathological changes and Rab3a expression in spinal cord tissue. Rab3a was overexpressed in the model rats to demonstrate its effect on SCI repair. Rab3a was also knocked down in neuronal cells to verify its role in vesicle secretion and neuronal cells. The binding protein of Rab3a was identified by Co-IP and mass spectrometry. RESULTS: Rab3a was significantly downregulated in SCI rats and Rab3a overexpression promoted SCI repair. Rab3a knockdown inhibited the secretion of neuronal cell-derived EVs. Compared to the EVs from the equal number of control neuronal cells, EVs from Rab3a-knockdown neuronal cells promoted M1 macrophage polarization, which in turn, promoted neuronal cell apoptosis. Mechanistically, STXBP1 was identified as a binding protein of Rab3a, and their interaction promoted the secretion of neuronal cell-derived EVs. Furthermore, METTL2b was significantly downregulated in SCI rats, and METTL2b knockdown significantly reduced Rab3a protein expression. CONCLUSION: These results suggest that Rab3a promotes the secretion of neuronal cell-derived EVs by interacting with its binding protein STXBP1. Neuronal cells-derived EVs inhibited the polarization of M1 macrophages in the spinal cord microenvironment, thereby promoting SCI repair. Our findings provide a theoretical basis for the clinical treatment of SCI.

Current perspectives of lncRNAs in abiotic and biotic stress tolerance in plants.

Abiotic/biotic stresses pose a major threat to agriculture and food security by impacting plant growth, productivity and quality. The discovery of extensive transcription of large RNA transcripts that do not code for proteins, termed long non-coding RNAs (lncRNAs) with sizes larger than 200 nucleotides in length, provides an important new perspective on the centrality of RNA in gene regulation. In plants, lncRNAs are widespread and fulfill multiple biological functions in stress response. In this paper, the research advances on the biological function of lncRNA in plant stress response were summarized, like as Natural Antisense Transcripts (NATs), Competing Endogenous RNAs (ceRNAs) and Chromatin Modification etc. And in plants, lncRNAs act as a key regulatory hub of several phytohormone pathways, integrating abscisic acid (ABA), jasmonate (JA), salicylic acid (SA) and redox signaling in response to many abiotic/biotic stresses. Moreover, conserved sequence motifs and structural motifs enriched within stress-responsive lncRNAs may also be responsible for the stress-responsive functions of lncRNAs, it will provide a new focus and strategy for lncRNA research. Taken together, we highlight the unique role of lncRNAs in integrating plant response to adverse environmental conditions with different aspects of plant growth and development. We envisage that an improved understanding of the mechanisms by which lncRNAs regulate plant stress response may further promote the development of unconventional approaches for breeding stress-resistant crops.