RESUMEN
Plant cell walls are a critical site where plants and pathogens continuously struggle for physiological dominance. Here we show that dynamic remodeling of pectin methylesterification of plant cell walls is a component of the physiological and co-evolutionary struggles between hosts and pathogens. A Phytophthora sojae secreted pectin methylesterase (PsPME1) decreases the degree of pectin methylesterification, thus synergizing with an endo-polygalacturonase (PsPG1) to weaken plant cell walls. To counter PsPME1-mediated susceptibility, a plant-derived pectin methylesterase inhibitor protein, GmPMI1, protects pectin to maintain a high methylesterification status. GmPMI1 protects plant cell walls from enzymatic degradation by inhibiting both soybean and P. sojae pectin methylesterases during infection. However, constitutive expression of GmPMI1 disrupted the tradeoff between host growth and defense responses. So, we used AlphaFold structure tools to design a modified form of GmPMI1 (GmPMI1R) which specifically targets and inhibits pectin methylesterases secreted from pathogens but not from the plants. Transient expression of GmPMI1R enhanced plant resistance to oomycetes and fungal pathogens. In summary, our work highlights biochemical modification of the cell wall as an important focal point in the physiological and co-evolutionary conflict between the hosts and microbes and serves as an important proof-of-concept for how rapid advancements in AI-driven structure-based tools can accelerate the prediction of new strategies for plant protection.
RESUMEN
Sphingosine-1 phosphate (S1P) is a lipid metabolite regulating diverse biological processes, including proliferation, differentiation, migration, and apoptosis, highlighting its physiological and therapeutic significance. Current S1P-based therapeutic approaches primarily focus on modulating the downstream signalling via targeting S1P receptors, however, this is challenged by incomplete receptor internalisation. Sphingosine-1-phosphate lyase (SPL) is a highly conserved enzyme that "gatekeeps" the final step of S1P degradation. Cognisant of the complex ligand and receptor interaction and dynamic metabolic networks, the selective modulation of SPL activity presents a new opportunity to regulate S1P biosynthesis and reveal its role in various systems. Over the past decade, an evolving effort has been made to identify new molecules that could block SPL activity in vitro or in vivo. This review focuses on summarising the current understanding of the reported SPL inhibitors identified through various screening approaches, discussing their efficacy in diverse model systems and the possible mechanism of action. Whilst effective modulation of S1P levels via inhibiting SPL is feasible, the specificity of those inhibitors remains inconclusive, presenting a clear challenge for future implications. Yet, none of the currently available SPL inhibitors is proven effective in elevating S1P levels within the central nervous system. This review article embraces future research focusing on investigating selective SPL inhibitors with high potency and possibly blood-brain-barrier permeability, which would aid the development of new S1P-based therapeutics for neurological disorders.
Asunto(s)
Aldehído-Liasas , Lisofosfolípidos , Esfingosina , Aldehído-Liasas/metabolismo , Aldehído-Liasas/antagonistas & inhibidores , Humanos , Animales , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
Digital technologies are changing how anatomy is taught tremendously. However, little is known about the effective integration of multimodal digital resources when concurrently provided in an anatomy course. To address this question, an array of digital anatomy resources including Augmented Reality (AR) and Virtual Reality (VR) anatomy resources were concurrently trialed by a total of 326 undergraduate and postgraduate students across three undergraduate (systemic anatomy, neuroanatomy, and regional anatomy) and one postgraduate anatomy (applied musculoskeletal anatomy) curricula in 2022. A five-point Likert scale learning and teaching survey was conducted to evaluate students' experiences, preferences, and perceptions. Most undergraduate (81% systemic anatomy, 76% neuroanatomy, and 87% regional anatomy) and postgraduate (97%) participants across the four cohorts felt confident in studying anatomy using digital resources and the majority (>80% undergraduate and >90% postgraduate) found the multimodal digital anatomy resources interactive and stimulating. The response showed that undergraduate (77% systemic anatomy, 81% neuroanatomy, and 97% regional anatomy) and postgraduate students (92%) consistently enjoyed their experience of using multimodal digital anatomy resources and thought that these resources enhanced their interest in studying anatomy. However, there are significant differences in ratings of specific digital resources among the junior (first-year undergraduates) and senior (third-year undergraduates and postgraduates) students. The virtual dissection table was uniformly preferred by the four cohorts of students across the board. Interestingly, however, VR anatomy and radiographic-based digital anatomy resources received diverse ratings. VR anatomy was valued most by junior undergraduate students (84%) who studied systemic anatomy compared to their senior counterparts (73%) who studied regional anatomy, whereas radiographic-based digital anatomy resources were more valued by the postgraduate students (93%) compared to undergraduates (65% systemic anatomy, 73% neuroanatomy, and 48% regional anatomy). This study identifies that while students uniformly appreciate the value of multimodal digital anatomy teaching, there is a clear difference in their perceptions towards individual resources, likely in a course-specific manner. We conclude that the selection and adoption of digital anatomy tools must be tailored as part of course design and that digital anatomy tools should be used in combination to provide an effective learning experience for students.
RESUMEN
The involvement of γδT cells, Th17 cells, and CD4+CD25+ regulatory T cells (Tregs) is crucial in the progression of pulmonary fibrosis (PF), particularly in maintaining immune tolerance and homeostasis. However, the dynamics of these cells in relation to PF progression, especially under pharmacological interventions, remains poorly understood. This study aims to unravel the interplay between the dynamic changes of these cells and the effect of pharmacological agents in a mouse model of PF induced by intratracheal instillation of bleomycin. We analyzed changes in lung histology, lung index, hydroxyproline levels, and the proportions of γδT cells, Th17 cells, and Tregs on the 3rd, 14th, and 28th days following treatment with Neferine, Isoliensinine, Pirfenidone, and Prednisolone. Our results demonstrate that these drugs can partially or dynamically reverse weight loss, decrease lung index and hydroxyproline levels, and ameliorate lung histopathological damage. Additionally, they significantly modulated the abnormal changes in γδT, Th17, and Treg cell proportions. Notably, on day 3, the proportion of γδT cells increased in the Neferine and Prednisolone groups but decreased in the Isoliensinine and Pirfenidone groups, while the proportion of Th17 cells decreased across all treated groups. On day 14, the Neferine group showed an increase in all three cell types, whereas the Pirfenidone group exhibited a decrease. In the Isoliensinine group, γδT and Th17 cells increased, and in the Prednisolone group, only Tregs increased. By day 28, an increase in Th17 cell proportion was observed in all treatment groups, with a decrease in γδT cells noted in the Neferine group. These shifts in cell proportions are consistent with the pathogenesis changes induced by these anti-PF drugs, suggesting a correlation between cellular dynamics and pharmacological interventions in PF progression. Our findings imply potential strategies for assessing the efficacy and timing of anti-PF treatments based on these cellular changes.
Asunto(s)
Bleomicina , Fibrosis Pulmonar , Linfocitos T Reguladores , Células Th17 , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th17/inmunología , Ratones , Piridonas/farmacología , Masculino , Prednisolona/farmacología , Progresión de la Enfermedad , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Pulmón/patología , Pulmón/inmunología , Pulmón/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Isoquinolinas/farmacología , Bencilisoquinolinas/farmacologíaRESUMEN
Previous studies have shown that the three-dimensional (3D) geometric and electronic structure of molecules play a crucial role in determining their key properties and intermolecular interactions. Therefore, it is necessary to establish a quantum chemical (QC) property database containing the most stable 3D geometric conformations and electronic structures of molecules. In this study, a high-quality QC property database, called QuanDB, was developed, which included structurally diverse molecular entities and featured a user-friendly interface. Currently, QuanDB contains 154,610 compounds sourced from public databases and scientific literature, with 10,125 scaffolds. The elemental composition comprises nine elements: H, C, O, N, P, S, F, Cl, and Br. For each molecule, QuanDB provides 53 global and 5 local QC properties and the most stable 3D conformation. These properties are divided into three categories: geometric structure, electronic structure, and thermodynamics. Geometric structure optimization and single point energy calculation at the theoretical level of B3LYP-D3(BJ)/6-311G(d)/SMD/water and B3LYP-D3(BJ)/def2-TZVP/SMD/water, respectively, were applied to ensure highly accurate calculations of QC properties, with the computational cost exceeding 107 core-hours. QuanDB provides high-value geometric and electronic structure information for use in molecular representation models, which are critical for machine-learning-based molecular design, thereby contributing to a comprehensive description of the chemical compound space. As a new high-quality dataset for QC properties, QuanDB is expected to become a benchmark tool for the training and optimization of machine learning models, thus further advancing the development of novel drugs and materials. QuanDB is freely available, without registration, at https://quandb.cmdrg.com/ .
RESUMEN
Multiplex PCR is a critical step when preparing amplicon library for next-generation sequencing. However, there are several challenges related to multiplex PCR including poor uniformity, nonspecific amplification, and primer-dimers. To address these issues, we propose a novel solution strategy that involves using a low cycle number (<10 cycles) in multiplex PCR and then employing carrier DNAs and magnetic beads for the selection of targeted products. This technique improves the amplicon uniformity while also reducing primer-dimers and PCR artifacts. To evaluate our technique, we initially utilized 120 DNA fragments from mouse genome containing single nucleotide polymorphism (SNP) sites. Sequencing results demonstrated that with only 7 cycles of multiplex PCR, 95.8% of the targeted SNP sites were mapped, with a coverage of at least 1×. The average sequencing depth of all amplicons was 1705.79 ± 1205.30×; 87% of them reached a coverage depth that exceeded 0.2-fold of the average sequencing depth. Our method had a greater uniformity (87%) when compared to Hi-Plex PCR (53.3%). Furthermore, we validated our strategy by randomly selecting 90 primer pairs twice from the initial set of 120 primer-pairs. Next, we used the same protocol to prepare amplicon libraries. The two groups had an average sequencing depth of 1013.30 ± 585.57× and 219.10 ± 158.27×, respectively; over 84% of the amplicons had a sequencing depth that exceeded 0.2-fold of average depth. These results suggest that the use of a low cycle number in multiplex PCR is a cost-effective and efficient approach for the preparation of amplicon libraries.
RESUMEN
To detect several RNA viruses simultaneously, a method based on multiplex ligation reaction combined with multiplex qPCR or multiplex PCR+capillary electrophoresis was established to detect four RNA viruses: human immunodeficiency virus (HIV), hepatitis C (HCV), influenza A virus (IAV) H1N1 and H5N1. The experimental conditions including ligation probe concentration, annealing procedure, ligation temperature and ligase dosage were optimized intensively. We found that the specificity of the ligation reaction was affected by the probe concentration predominantly, high-probe concentration (100 nM) resulted in splint-independent ligation with efficiency comparable to that with RNA splint. The sensitivity of the ligation reaction was affected by the annealing mode apparently as the sensitivity of the step-down annealing mode was 100 times higher than that of the isothermal annealing at 37 °C. Under the optimized condition, this assay could detect virus RNA as low as 16 viral copies per reaction in doubleplex and triplex real-time quantitative PCR detection with satisfactory specificity and precision. By multiplex PCR+capillary electrophoresis, four RNA viruses could be detected in one tube with the sensitivity of 10 copies per reaction.
Asunto(s)
Hepatitis C , Subtipo H1N1 del Virus de la Influenza A , Subtipo H5N1 del Virus de la Influenza A , Virus ARN , Humanos , Virus ARN/genética , ARN Viral/genética , Reacción en Cadena de la Polimerasa MultiplexRESUMEN
Enantiopure α-substituted phosphonic acids are widely utilized as drugs, pesticides, and ligands. Despite numerous synthetic approaches having been investigated, precise construction of P-adjacent chiral tertiary carbon centres by the employment of recoverable chiral auxiliaries is traditional and still one of the most reliable and practical synthetic methodologies so far. Herein, we present a highly diastereoselective synthesis of α-substituted phosphonates via the unique CAMDOL-derived P-substrates by an efficient sequential deprotonation with LiHMDS and alkylation/arylation with RI. A wide range of 30 structurally diverse α-substituted phosphonate products, including the well-known P-analogues of naproxen and ibuprofen, were thus afforded conveniently in up to 92% yields and 99 : 1 diastereomeric ratios. The related chiral phosphonic acid could be easily obtained by simple acidic hydrolysis with fully recovered auxiliary. This CAMDOL-enabled asymmetric synthetic protocol exhibits comparative advantages over known chiral-induction methods with easy accessibility and compatibility of furnishing a variety of C-stereogenic centres in the proximity of the phosphorus atom, including some rare examples.
RESUMEN
The flipped classroom teaching model has been widely used in anatomy education to embrace a blended learning strategy. However, the impact that a continuous flipped classroom teaching model exerts on student learning of human topographic anatomy remains unclear. To address this question, student learning experience and performance were compared between third-year undergraduate students who participated in a continuous flipped anatomy classroom teaching since their first year (n = 65, experimental group) and those under the flipped anatomy teaching model only in their third year (n = 45, control group). A five-point Likert scale learning and teaching survey was conducted to evaluate students' perceptions of the flipped classroom model. Students under a continuous flipped classroom teaching model rated significantly higher on the impact of the flipped model on learning difficult anatomy concepts than the control group (*p = 0.0346). The rating on independent learning remained not statistically different between the two groups, although a trend difference was detected (p = 0.0604). Analysis of learning performance revealed that the experimental group significantly outperformed the control group when answering questions focusing on regional anatomy (*p = 0.0207). No significant difference was identified in students' marks of case-based studies between the two groups. In summary, the results of this study indicate that the flipped classroom model implemented over a long term continues to advance students' learning experience and performance in anatomy, indicating a "dose" effect on active learning. The findings of this study will assist the best practices of the flipped anatomy classroom and develop evidence-informed approaches to advance anatomy education in the future.
Asunto(s)
Anatomía , Humanos , Anatomía/educación , Estudiantes , Aprendizaje Basado en Problemas/métodos , Curriculum , Escolaridad , EnseñanzaRESUMEN
Anatomists are facing a new generation of learners who will study and work in a technology-rich environment. Indeed, digital technologies are tremendously changing how information and knowledge are communicated and retrieved. However, it remains unclear whether an anatomy assessment can be designed to promote contextual learning through integrating a digital communication strategy. To investigate this, assessment methods were diversified in the first-year neuroanatomy and third-year regional anatomy curricula through implementing a multimedia human anatomy group assignment integrating digital literacies and scientific communication. Through completing this multimedia assignment, students demonstrated their anatomy knowledge transfer using a range of approaches. The main mode of presentations chosen in the two anatomy units were non-animated video presentations (~50%), animated video presentations (~30%), storyboards (~10%), podcasts (~3%), and filmed videos (~3%). A 5-point Likert scale learning and teaching survey was conducted for a total of 195 undergraduate health science students to evaluate students' perception of this group assignment. The majority of students (70-80%) strongly agreed or agreed that the multimedia group assignment helped their teamwork skills. Students who produced animated videos significantly outperformed those who adopted the non-animated presentations during the end-of-semester theory examination (p < 0.05). This study demonstrates that an anatomy group assignment integrating digital literacy and scientific communication is an effective assessment strategy associated with a positive learning experience and outcome. This inquiry-based assignment promotes learning through assessment, allowing students to not only consolidate and extend anatomy knowledge but also developing effective digital communication skills, providing new insights into non-didactic anatomy assessments.
Asunto(s)
Anatomía , Multimedia , Humanos , Alfabetización , Anatomía/educación , Aprendizaje , ComunicaciónRESUMEN
The cabbage white butterfly (Pieris rapae), a major agricultural pest, has become one of the most abundant and destructive butterflies in the world. It is widely distributed in a large variety of climates and terrains of China due to its strong adaptability. To gain insight into the population genetic characteristics of P. rapae in China, we resequenced the genome of 51 individuals from 19 areas throughout China. Using population genomics approaches, a dense variant map of P. rapae was observed, indicating a high level of polymorphism that could result in adaptation to a changing environment. The feature of the genetic structure suggested considerable genetic admixture in different geographical groups. Additionally, our analyses suggest that physical barriers may have played a more important role than geographic distance in driving genetic differentiation. Population history showed the effective population size of P. rapae was greatly affected by global temperature changes, with mild periods (i.e., temperatures warmer than those during glaciation but not excessively hot) leading to an increase in population size. Furthermore, by comparing populations from south and north China, we have identified selected genes related to sensing temperature, growth, neuromodulation and immune response, which may reveal the genetic basis of adaptation to different environments. Our study is the first to illustrate the genetic signatures of P. rapae in China at the population genomic level, providing fundamental knowledge of the genetic diversity and adaptation of P. rapae.
Asunto(s)
Brassica , Mariposas Diurnas , Humanos , Animales , Mariposas Diurnas/genética , Metagenómica , Biodiversidad , Temperatura , Variación GenéticaRESUMEN
Being the highest expressed neurotrophin in the mammalian brain, the brain-derived neurotrophic factor (BDNF) is essential to neural development and plasticity in both health and diseases. Following the discovery of BDNF by Yves-Alain Barde in 1982, the main feature of BDNF's activity in myelination was first described by Cellerino et al. in 1997. Since then, genetic manipulation of the BDNF-encoding gene and its receptors in murine models has revealed the contribution of BDNF to the myelinating process in the central nervous system (CNS). The series of BDNF or receptor mouse mutants as well as the BDNF polymorphism in humans have provided new insights into the roles that BDNF signaling plays in myelination in a complex manner. 2024 marks the 30th year of BDNF's research in myelination. Here, we share our perspective on the 30-year history of BDNF in the field of CNS myelination from phenotyping to therapeutic development, focusing on genetic evidence regarding the mechanism by which BDNF regulates myelin formation and repair in the CNS. This review also discusses the current hypotheses of BDNF's action on CNS myelination: axonal- and oligodendroglial-driven mechanisms, which may be ultimately activity-dependent. Last, this review raises the challenges and opportunities of developing BDNF-based therapies for neurodegenerative diseases, opening unanswered questions for future investigation.
RESUMEN
The role of cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 (CAP) superfamily proteins in the innate immune responses of mammals is well characterized. However, the biological function of CAP superfamily proteins in plant-microbe interactions is poorly understood. We used proteomics and transcriptome analyses to dissect the apoplastic effectors secreted by the oomycete Phytophthora sojae during early infection of soybean leaves. By transiently expressing these effectors in Nicotiana benthamiana, we identified PsCAP1, a novel type of secreted CAP protein that triggers immune responses in multiple solanaceous plants including N. benthamiana. This secreted CAP protein is conserved among oomycetes, and multiple PsCAP1 homologs can be recognized by N. benthamiana. PsCAP1-triggered immune responses depend on the N-terminal immunogenic fragment (aa 27-151). Pretreatment of N. benthamiana with PsCAP1 or the immunogenic fragment increases plant resistance against Phytophthora. The recognition of PsCAP1 and different homologs requires the leucine-rich repeat receptor-like protein RCAP1, which associates with two central receptor-like kinases BRI1-associated receptor kinase 1 (BAK1) and suppressor of BIR1-1 (SOBIR1) in planta. These findings suggest that the CAP-type apoplastic effectors act as an important player in plant-microbe interactions that can be perceived by plant membrane-localized receptor to activate plant resistance.
Asunto(s)
Proteínas Repetidas Ricas en Leucina , Phytophthora , Animales , Nicotiana/genética , Leucina , Inmunidad Innata , MamíferosRESUMEN
Artificial cell spheroids are gaining importance in tissue engineering and regenerative medicine fields. Biomimetic construction of stem cell spheroids is nevertheless challenging, and bioplatforms permitting controllable and high-efficient fabrication of functional stem cell spheroids are needed. Here, a fractal nanofiber-based bioplatform is developed based on a tunable interfacial-induced crystallization approach, allowing a programmed culture of artificial stem cell spheroids under an ultralow cell seeding density. Specifically, starting with the nanofibers of poly(L-lactide) (PLLA) and gelatin (PmGn), an interfacial growth of PLLA nanocrystals is subsequently performed to construct the fractal nanofiber-based biotemplates (C-PmGn). Cell experiments with human dental pulp stem cells (hDPSCs) demonstrate that the fractal C-PmGn could effectively decrease cell-matrix interactions, thus facilitating spontaneous cell spheroid formation even under a low cell seeding density (1 × 104 cells/cm2). Nanotopological properties of the C-PmGn bioplatform can be tuned by adjusting the fractal degree, thus enabling its suitability for the 3D culture of diverse hDPSC spheroids. Such a strategy provides a relatively simple and low-cost option for formation, expansion, and utility of stem cell spheroids. It offers another promising pathway to advance the development of stem cell therapies.
Asunto(s)
Nanofibras , Esferoides Celulares , Humanos , Nanofibras/química , Cristalización , Fractales , Células MadreRESUMEN
Sphingosine 1-phosphate lyase (SPL) is the terminal enzyme that controls the degradation of the bioactive lipid sphingosine 1-phosphate (S1P) within an interconnected sphingolipid metabolic network. The unique metabolic position of SPL in maintaining S1P levels implies SPL could be an emerging new therapeutic target. Over the past decade, an evolving effort has been made to unravel the role of SPL in the nervous system; however, to what extent SPL influences the developing and mature nervous system through altering S1P biosynthesis remains opaque. While congenital SPL deletion is associated with deficits in the developing nervous system, the loss of SPL activity in adults appears to be neuroprotective in acquired neurological disorders. The controversial findings concerning SPL's role in the nervous system are further constrained by the current genetic and pharmacological tools. This review attempts to focus on the multi-faceted nature of SPL function in the mammalian nervous systems, implying its dichotomy in the developing and adult central nervous system (CNS). This article also highlights SPL is emerging as a therapeutic molecule that can be selectively targeted to modulate S1P for the treatment of acquired neurodegenerative diseases, raising new questions for future investigation. The development of cell-specific inducible conditional SPL mutants and selective pharmacological tools will allow the precise understanding of SPL's function in the adult CNS, which will aid the development of a new strategy focusing on S1P-based therapies for neuroprotection.
Asunto(s)
Sistema Nervioso Central , Lisofosfolípidos , Animales , Esfingosina , Neuroprotección , Espironolactona , MamíferosRESUMEN
Backgrounds: Liensinine (Lien), Neferine (Nef), Isoliensinine (Iso) and Tetrandrine (Tet), benzylisoquinoline alkaloids (BIAs), have been shown inhibitory effects on pulmonary fibrosis (PF) through anti-inflammatory, anti-oxidative activities, inhibition of cytokines and NF-κB. Effects of other similar BIAs, Dauricine (Dau), Papaverine (Pap) and lotusine (Lot), on PF remain unclear. Here, we explored the effects of five bisbenzylisoquinoline (Lien, Nef, Iso, Tet and Dau) and two monobenzylisoquinoline (Pap, Lot) alkaloids on normal and PF fibroblasts. Methods: Primary normal and PF lung fibroblasts were cultured and treated with these alkaloids. Proliferation, activation, migration and apoptosis changes were detected by MTT, wound healing assay, flow cytometry. Protein level was analyzed by Western blot. Results: All BIAs inhibited proliferation of normal and PF lung fibroblasts induced by TGF-ß. α-SMA protein level in normal and PF lung fibroblasts decreased after Lien, Nef, Iso, Tet and Dau treatment. Pap and Lot had no influence on α-SMA expression. Dau showed the strongest inhibitory effects on proliferation and activation among alkaloids. The migration rates of normal and PF lung fibroblasts were inhibited by Lien, Nef, Iso, and Dau. Lien, Nef, Iso and Dau significantly promoted apoptosis, while Tet had no effect on apoptosis. Pap and Lot had no influence on activation, migration and apoptosis. Dau significantly inhibited Smad3/4 and p-ERK1/2 protein overexpression induced by TGF-ß1. Conclusions: Bisbenzylisoquinoline alkaloids had stronger effects on inhibiting lung fibroblasts than monobenzylisoquinoline alkaloids. Dau expressed the strongest inhibitory effects, which may be related to its inhibition of TGF-ß1/Smad3/4 and p-ERK1/2 pathway proteins.
RESUMEN
The access to P-stereogenic motifs has always been considered a very challenging and high attractive mission in modern organic synthesis. While several chiral auxiliaries employed by the practical Jugé-Stephan-like methodology have been developed, new type of readily accessible bifunctional ligands toward P-stereogenic building still remain much desirable. Herein, we present a powerful chiral template, camphor-derived 2,3-diols named CAMDOL, which were designed and synthesized from the commercially cheap camphorquinone in high yields at 50 grams scale with a column-free purification. Diverse P(III)-chiral compounds and their borane forms including phosphinous acids, phosphinites, and phosphines, as well as the corresponding P(V)-chiral compounds including phosphinates, phosphine oxides, phosphinothioates, phosphine sulfides, and secondary phosphine oxides were afforded in high yields and ee values through the optimal 2,3-diphenyl CAMDOL platform. An unusual C3-OP bond cleavage following the first P-OC2 bond breaking was observed during the ring-opening process when quenching by NH4Cl solution, which generates a unique but valuable camphor-epoxide scaffold as by-product.
RESUMEN
α,ß-Unsaturated esters are key structural motifs widely distributed in various biologically active molecules, and their Z/E-stereoselective synthesis has always been considered highly attractive in organic synthesis. Herein, we present a >99% (E)-stereoselective one-pot synthetic approach towards ß-phosphoroxylated α,ß-unsaturated esters via a mild trimethylamine-catalyzed 1,3-hydrogen migration of the corresponding unconjugated intermediates derived from the solvent-free Perkow reaction between low-cost 4-chloroacetoacetates and phosphites. Versatile ß,ß-disubstituted (E)-α,ß-unsaturated esters were thus afforded with full (E)-stereoretentivity by cleavage of the phosphoenol linkage via Negishi cross-coupling. Moreover, a stereoretentive (E)-rich mixture of a α,ß-unsaturated ester derived from 2-chloroacetoacetate was obtained and both isomers were easily afforded in one operation.
RESUMEN
OBJECTIVE: Older adults with subjective memory complaints (SMC) have a higher risk of dementia and commonly demonstrate symptoms of anxiety. This study examined the neural correlates of group counseling (GC)-boosted memory training (MT) gains. DESIGN: This study was an active, controlled, randomized trial. SETTING: Neighborhoods near the Institute of Psychology of the Chinese Academy of Sciences (CAS). PARTICIPANTS: Community-dwelling older adults, aged 60 or above with a minimum of 6 years of education, were recruited through advertisements and flyers posted at community service stations. MEASUREMENTS: The amplitude of low-frequency fluctuations and resting-state functional connectivity (rs-FC) analyses were used to examine the neural correlates associated with MT gains enhanced by improved mood in older adults with SMC. Participants were randomly assigned to the combined intervention (CI) or GC group. The CI group received 3 weeks of GC followed by 4 weeks of MT, and the GC group received GC and health lectures. Cognitive function and emotions were assessed before GC (T1), after GC (T2), and after MT (T3). Both groups underwent resting-state functional magnetic resonance imaging scanning at T2 and T3. RESULTS: Alleviated anxiety was positively correlated with rs-FC between the amygdala and left hippocampus and negatively correlated with rs-FC between the amygdala and right hippocampus. MT improvement was negatively correlated with rs-FC between the amygdala and right hippocampus in the CI group; the correlation was not significant after controlling for emotional changes. CONCLUSIONS: Amygdala-hippocampal connectivity may be associated with improved mood-enhanced MT gains in individuals with SMC.