Asymmetric Cross-Coupling of Aldehydes with Diverse Carbonyl or Iminyl Compounds by Photoredox-Mediated Cobalt Catalysis.

The asymmetric cross-coupling of unsaturated bonds, hampered by their comparable polarity and reactivity, as well as the scarcity of efficient catalytic systems capable of diastereo- and enantiocontrol, presents a significant hurdle in organic synthesis. In this study, we introduce a highly adaptable photochemical cobalt catalysis framework that facilitates chemo- and stereoselective reductive cross-couplings between common aldehydes with a broad array of carbonyl and iminyl compounds, including N-acylhydrazones, aryl ketones, aldehydes, and α-keto esters. Our methodology hinges on a synergistic mechanism driven by photoredox-induced single-electron reduction and subsequent radical-radical coupling, all precisely guided by a chiral cobalt catalyst. Various optically enriched ß-amino alcohols and unsymmetrical 1,2-diol derivatives (80 examples) have been synthesized with good yields (up to 90% yield) and high stereoselectivities (up to >20:1 dr, 99% ee). Of particular note, this approach accomplishes unattainable photochemical asymmetric transformations of aldehydes with disparate carbonyl partners without reliance on any external photosensitizer, thereby further emphasizing its versatility and cost-efficiency.

Calpain-2 Mediates MBNL2 Degradation and a Developmental RNA Processing Program in Neurodegeneration.

Increasing loss of structure and function of neurons and decline in cognitive function is commonly seen during the progression of neurologic diseases, although the causes and initial symptoms of individual diseases are distinct. This observation suggests a convergence of common degenerative features. In myotonic dystrophy type 1 (DM1), the expression of expanded CUG RNA induces neurotransmission dysfunction before axon and dendrite degeneration and reduced MBNL2 expression associated with aberrant alternative splicing. The role of loss of function of MBNL2 in the pathogenesis of neurodegeneration and the causal mechanism of neurodegeneration-reduced expression of MBNL2 remain elusive. Here, we show that increased MBNL2 expression is associated with neuronal maturation and required for neuronal morphogenesis and the fetal to adult developmental transition of RNA processing. Neurodegenerative conditions including NMDA receptor (NMDAR)-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuclear translocation of calpain-2, thus resulting in MBNL2 degradation and reversal of MBNL2-regulated RNA processing to developmental patterns. Nuclear expression of calpain-2 resembled its developmental pattern and was associated with MBNL2 degradation. Knock-down of calpain-2 expression or inhibition of calpain-2 nuclear translocation prevented neurodegeneration-reduced MBNL2 expression and dysregulated RNA processing. Increased calpain-2 nuclear translocation associated with reduced MBNL2 expression and aberrant RNA processing occurred in models for DM1 and Alzheimer's disease (AD) including EpA960/CaMKII-Cre mice of either sex and female APP/PS1 and THY-Tau22 mice. Our results identify a regulatory mechanism for MBNL2 downregulation and suggest that calpain-2-mediated MBNL2 degradation accompanied by re-induction of a developmental RNA processing program may be a converging pathway to neurodegeneration.SIGNIFICANCE STATEMENT Neurologic diseases share many features during disease progression, such as cognitive decline and brain atrophy, which suggests a common pathway for developing degenerative features. Here, we show that the neurodegenerative conditions glutamate-induced excitotoxicity and dysregulated calcium homeostasis induced translocation of the cysteine protease calpain-2 into the nucleus, resulting in MBNL2 degradation and reversal of MBNL2-regulated RNA processing to an embryonic pattern. Knock-down or inhibition of nuclear translocation of calpain-2 prevented MBNL2 degradation and maintained MBNL2-regulated RNA processing in the adult pattern. Models of myotonic dystrophy and Alzheimer's disease (AD) also showed calpain-2-mediated MBNL2 degradation and a developmental RNA processing program. Our studies suggest MBNL2 function disrupted by calpain-2 as a common pathway, thus providing an alternative therapeutic strategy for neurodegeneration.

Fe-Catalyzed Aliphatic C-H Methylation of Glycine Derivatives and Peptides.

Direct and selective C-H methylation is a powerful tool with which to install methyl groups into organic molecules, and is particularly useful in pharmaceutical chemistry. However, practical methods for such modification of biologically interesting targets have been rarely developed. We here report an iron-catalyzed C(sp3 )-H methylation reaction of glycine derivatives, peptides and drug-like molecules in an alcohol in the presence of di-tert-butyl peroxide. A readily available iron catalyst plays multiple roles in the transformation, which accelerates oxidation of C-N bonds to C=N double bonds, activates imine intermediates as Lewis acids by bidentate chelation, and at the same time facilitates cleavage of the peroxide to generate methyl radicals. A variety of methylated N-aryl glycine derivatives and peptides were obtained in good yield and with excellent chemo- and site-selectivity. This reaction is scalable, easily managed, and can be completed within 1-2 h. It features an economic, bio-friendly catalyst, a green solvent and low toxic reagents, and will provide effective access to precise C-H modification of biomolecules and natural products.

Photo-Induced C-H Methylation Reactions.

Direct C-H methylation is a highly valuable approach for introducing methyl groups into organic molecules, particularly in pharmaceutical chemistry. Among the various methodologies available, photo-induced methylation stands out as an exceptional choice due to its mild reaction conditions, energy efficiency, and compatibility with functional groups. This article offers a comprehensive review of photochemical strategies employed for the direct and selective methylation of C(sp3 )-H, C(sp2 )-H, and C(sp)-H bonds in various organic molecules. The discussed methodologies encompass transition-metal-based photocatalysis, organophotocatalysis, as well as other metal-free approaches, including electron donor-acceptor (EDA)-enabled transformations. Importantly, a wide range of easily accessible agents such as tert-butyl peroxide, methanol, DMSO, methyl tert-butyl ether, TsOMe, N-(acetoxy)phthalimide, acetic acid, methyl halides, and even methane can serve as effective methylating reagents for modifying diverse targets. These advancements in photochemical C-H methylation are anticipated to drive further progress in the fields of organic synthesis, photocatalysis, and pharmaceutical development, opening up exciting avenues for creating novel organic molecules and discovering new drug compounds.

Recent Advances in Photochemical Asymmetric Three-Component Reactions.

Over the past decades, asymmetric photochemical synthesis has garnered significant attention for its sustainability and unique ability to generate enantio-enriched molecules through distinct reaction pathways. Photochemical asymmetric three-component reactions have demonstrated significant potential for the rapid construction of chiral compounds with molecular diversity and complexity. However, noteworthy challenges persist, including the participation of high-energy intermediates such as radical species, difficulties in precise control of stereoselectivity, and the presence of competing background and side reactions. Recent breakthroughs have led to the development of sophisticated strategies in this field. This review explores the intricate mechanisms, synthetic applications, and limitations of these methods. We anticipate that it will contribute towards advancing asymmetric catalysis, photochemical synthesis, and green chemistry.

Effect of individualized PEEP titration by ultrasonography on perioperative pulmonary protection and postoperative cognitive function in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To evaluate the effect of the individualized positive end-expiratory pressure (PEEP) lung protection ventilation strategy by combining driving pressure (ΔP) and pulmonary ultrasound (LUS)-based titration on lung function and postoperative cognitive function in patients with chronic obstructive pulmonary disease (COPD) during laparoscopic surgery. METHODS: A total of 108 patients with COPD undergoing laparoscopic gastrointestinal surgery under general anesthesia were included in this study. They were randomly divided into three groups (n = 36): traditional volume ventilation group (Group C), fixed PEEP 5 cmH2O group (Group P), and ΔP combined with LUS-based PEEP titration in the resuscitation room group (Group T). All three groups were given volume ventilation mode, I:E = 1:2; In group C, VT was 10 mL/kg and PEEP was 0 cmH2O; In groups P and T, VT was 6 mL/kg and PEEP was 5 cmH2O; After mechanical ventilation for 15 min in Group T, ΔP in combination with LUS was used to titrate PEEP. The oxygenation index (PaO2/FiO2), airway platform pressure (Pplat), dynamic lung compliance (Cdyn), Montreal Cognitive Assessment (MoCA), and venous interleukin-6(IL-6) were recorded at the corresponding time points, and the final PEEP value in Group T was recorded. RESULTS: The final PEEP value of Group T was (6.4 ± 1.2) cmH2O; Compared with groups C and P: PaO2/FiO2 and Cdyn in Group T were significantly increased (P < 0.05) and value of IL-6 was significantly decreased (P < 0.05) at the corresponding time points. Compared with group C, the MoCA score on day 7 after surgery in Group T was significantly higher (P < 0.05). CONCLUSION: Compared with the traditional ventilation strategy, the individualized ΔP combined with LUS-based PEEP titration in patients with COPD during the perioperative period of laparoscopic surgery can play a better role in lung protection and can improve postoperative cognitive function.

Selective Difunctionalization of Unactivated Aliphatic Alkenes Enabled by a Metal-Metallaaromatic Catalytic System.

The design of organometallic catalysts is crucial in the development of catalytic reactions. Herein, we describe a heterometallic [Os-Cu] complex with the characteristics of bimetallics, metallaaromatics, and pincer complexes. This complex serves as a highly effective catalyst for selective amino- and oxyselenation of unactivated alkenes. More than 80 examples including challenging substrates of unsymmetric aliphatic alkenes and amine-based nucleophiles in such reactions are provided. These reactions produce 1,2-difunctionalized products with good yields and high levels of chemo-, regio-, and stereoselectivity. Our studies revealed the following: (i) The usually inert osmium center activates the N- or O-centered nucleophiles. (ii) The copper-osmium bonding and its cooperative effects play essential roles in control the selectivity by bringing the reaction components into close proximity. (iii) The metallaaromatic moiety helps to stabilize the intermediate. These findings provide a versatile platform for catalyst design based on metal-metallaaromatic cooperative effects that have not been attained previously with bimetallic complexes.

CELF1 promotes vascular endothelial growth factor degradation resulting in impaired microvasculature in heart failure.

Vascular rarefaction due to impaired angiogenesis is associated with contractile dysfunction and the transition from compensation to decompensation and heart failure. The regulatory mechanism controlling vascular rarefaction during the transition remains elusive. Increased expression of a nuclear RNA-binding protein CUGBP Elav-like family member 1 (CELF1) in the adult heart is associated with the transition from compensated hypertrophy to decompensated heart failure. Elevated CELF1 level resulted in degradation of the major cardiac gap junction protein, connexin 43, in dilated cardiomyopathy (DCM), the most common cause of heart failure. In the present study, we investigated the role of increased CELF1 expression in causing vascular rarefaction in DCM. CELF1 overexpression (CELF1-OE) in cardiomyocytes resulted in reduced capillary density. CELF1-OE mice administered hypoxyprobe showed immunoreactivity and increased mRNA levels of HIF1α, Glut-1, and Pdk-1, which suggested the association of a reduced capillary density-induced hypoxic condition with CELF1 overexpression. Vegfa mRNA level was downregulated in mouse hearts exhibiting DCM, including CELF1-OE and infarcted hearts. Vegfa mRNA level was also downregulated to a similar extent in cardiomyocytes isolated from infarcted hearts by Langendorff preparation, which suggested cardiomyocyte-derived Vegfa expression mediated by CELF1. Cardiomyocyte-specific depletion of CELF1 preserved the capillary density and Vegfa mRNA level in infarcted mouse hearts. Also, CELF1 bound to Vegfa mRNA and regulated Vegfa mRNA stability via the 3' untranslated region. These results suggest that elevated CELF1 level has dual effects on impairing the functions of cardiomyocytes and microvasculature in DCM.

Effect of doxofylline on pulmonary inflammatory response and oxidative stress during mechanical ventilation in rats with COPD.

OBJECTIVE: To evaluate the effects of doxofylline on inflammatory responses and oxidative stress during mechanical ventilation in rats with chronic obstructive pulmonary disease (COPD). METHODS: Eight-week-old male Sprague Dawley rats were selected, and the COPD rat model was constructed. The rats were randomly divided into a model group (group M), a model + normal saline group (group N), a doxofylline group (group D), and a control group fed with conventional chow and given normal oxygen supply (group C) (n = 12 in each group). Tracheal intubation and mechanical ventilation were conducted in the rats in each group after anesthesia. A real-time intravenous infusion with 50 mg/kg of doxofylline was conducted in group D, and there was no drug intervention in groups C, N and M. Pathological manifestations of the pulmonary tissues were observed and compared among the groups. And some indicators were evaluated. RESULTS: (1) The pulmonary tissues of the rats in groups M, N, and D exhibited typical pathological histological changes of COPD. (2) Groups M, N, and D showed increased Ppeak, PaCO2, total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue and BALF, and decreased PaO2 and IL-10 and SOD levels, compared with group C. (3). Group D showed decreased Ppeak, PaCO2, total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue, and increased PaO2 and IL-10 and SOD levels, compared with group N or M. CONCLUSION: Doxofylline was shown to improve ventilation and air exchange during mechanical ventilation in rats with COPD, reduce the inflammatory response and oxidative stress, and mitigate the degree of pulmonary tissue injury.

Condensed Osmaquinolines with NIR-II Absorption Synthesized by Aryl C-H Annulation and Aromatization.

The structural design and tuning of properties of metallaaromatics are crucial in materials and energy science. Herein, we describe the rapid synthesis of tetracyclic metallaaromatics containing quinoline and pentalene motifs fused by a metal-bridged fragment. These unique compounds display remarkably broad absorption, enabling for the first time the absorption of metallaaromatics to reach the second near-infrared (NIR-II) bio-window. The formation of osmaquinoline unit involves an unconventional C(sp2 )-C(sp3 ) coupling promoted by AgBF4 to achieve [3+3] cycloaddition. The introduction of cyclic dπ -pπ conjugation and extension of the aromatic π-framework can effectively shrink the HOMO-LUMO gap, thus broadening the absorption window. The considerable photothermal conversion efficiency (PCE) in both the NIR-I and NIR-II windows, the high photothermal stability and the excellent electrochemical behavior suggest many potential applications of these condensed metallaquinolines.

Isomerization in Alkynyl-Protected Gold Nanoclusters.

We report the controlled synthesis and structures of two isomeric gold nanoclusters, whose compositions are determined to be Au23(C≡CBut)15 (denoted as Au23-1 and Au23-2) by single-crystal X-ray diffraction and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. This is the first time isomerism is discovered in alkynyl-protected gold nanoclusters. The metal-to-ligand ratios in these two clusters are different from known Aun(SR)m systems and have not been observed in the Aux(C≡CPh)y family. This pair of isomers exhibits different optical properties, although they have similar structures and identical components. For both Au23 clusters, time-dependent density functional theory calculations revealed the frontier orbitals highest occupied molecular orbital (HOMO)-1, HOMO, and lowest unoccupied molecular orbital (LUMO) are mainly constructed from the Au15 kernel and V-shaped alkynyl-gold motifs. The HOMO → LUMO transition of Au23-1 is optically forbidden, whereas it is allowed in Au23-2. It is also found that Au23-2 cluster can be transformed to Au23-1 spontaneously under ambient conditions. This work offers further insight into the synthesis and isomerism of all-alkynyl-protected gold nanoclusters and will stimulate more investigation of isomeric metal nanoclusters.

Reduced cytoplasmic MBNL1 is an early event in a brain-specific mouse model of myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats in the 3' untranslated region (UTR) of the dystrophia myotonia protein kinase (DMPK) gene. Cognitive impairment associated with structural change in the brain is prevalent in DM1. How this histopathological abnormality during disease progression develops remains elusive. Nuclear accumulation of mutant DMPK mRNA containing expanded CUG RNA disrupting the cytoplasmic and nuclear activities of muscleblind-like (MBNL) protein has been implicated in DM1 neural pathogenesis. The association between MBNL dysfunction and morphological changes has not been investigated. We generated a mouse model for postnatal expression of expanded CUG RNA in the brain that recapitulates the features of the DM1 brain, including the formation of nuclear RNA and MBNL foci, learning disability, brain atrophy and misregulated alternative splicing. Characterization of the pathological abnormalities by a time-course study revealed that hippocampus-related learning and synaptic potentiation were impaired before structural changes in the brain, followed by brain atrophy associated with progressive reduction of axon and dendrite integrity. Moreover, cytoplasmic MBNL1 distribution on dendrites decreased before dendrite degeneration, whereas reduced MBNL2 expression and altered MBNL-regulated alternative splicing was evident after degeneration. These results suggest that the expression of expanded CUG RNA in the DM1 brain results in neurodegenerative processes, with reduced cytoplasmic MBNL1 as an early event response to expanded CUG RNA.

Access to Metal-Bridged Osmathiazine Derivatives by a Formal [4+2] Cyclization.

Treatment of osmacyclopentadiene derivatives 1 with phenyl or isopropyl isothiocyanate gave the fused five and six-membered osmacycles 2-5 by a formal [4+2] cyclization. The facile protonation of the newly generated exocyclic imine in complexes 2-5 afforded conjugation-extended osmacycle derivatives 6-9. Compounds 2-9 each contain two main-group heteroatoms (N and S) in the fused six-membered ring located at the ortho (for S) and para (for N) positions relative to the osmium centre; these species can be regarded as rare osma-1,3-thiazine derivatives and represent the first fused metallathiazine derivatives. In contrast to the non-planar organic 6H-1,3-thiazine, nearly coplanar metallathiazines 8 and 9 can be achieved by tuning the groups on the two nitrogen atoms. These unique metal-bridged osma-1,3-thiazine derivatives exhibit remarkable stabilities, broad spectral absorptions spanning the visible spectra, and considerable photothermal properties, which suggests their potential applications in material science.

Ligand-Controlled Doping Effects in Alloy Nanoclusters Au4 Ag23 and Au5 Ag24.

The syntheses and properties of two bimetallic nanoclusters [Au4 Ag23 (C≡CtBu)10 (dppf)4 Cl7 ](PF6 )2 and [Au5 Ag24 (C≡CC6 H4 -p-tBu)16 (dppf)4 Cl4 ](PF6 )3 are reported. The Au atoms distributed in both the cores and the surface motifs are clearly determined. The two nanoclusters show distinctly different geometric structures and electronic properties, which are attributed to the subtle changes in the surface alkynyl structures.

Au57 Ag53 (C≡CPh)40 Br12 : A Large Nanocluster with C1 Symmetry.

The controlled synthesis and structure determination of a bimetallic nanocluster Au57 Ag53 (C≡CPh)40 Br12 (Au57 Ag53 ) is presented. The metal core has a four-shell Au2 M3 @Au34 @Ag51 @Au20 (M=1/3 Au+2/3 Ag) architecture. In contrast to the previously reported large nanoclusters that have highly symmetric kernel structures, the metal atoms in Au57 Ag53 are arranged in an irregular manner with C1 symmetry. This cluster exhibits excellent thermal stability and is robust under oxidative or basic conditions. The silver precursors play a key role in dictating the structures of the nanoclusters, which suggests the importance of the counteranions used.

Chloride-Promoted Formation of a Bimetallic Nanocluster Au80Ag30 and the Total Structure Determination.

We report the total structure determination of a large bimetallic nanocluster with an overall composition of [Au80Ag30(C≡CPh)42Cl9]Cl. It is the largest structurally characterized bimetallic coinage nanocluster so far. The 110 metal atoms are distributed in a concentric four-shell Russian doll arrangement, Au6@Au35@Ag30Au18@Au21. There are 42 PhC≡C- ligands and 9 µ2-chloride ligands clamping on the cluster surface. The chloride is proven to be critical for the formation of this giant cluster, as the control experiment in the absence of halide gives only smaller species. This work demonstrates that the halide can play a key role in the formation of a large metal nanocluster, and the halide effect should be considered in the design and synthesis of metal nanoclusters.

Role of Anions Associated with the Formation and Properties of Silver Clusters.

Metal clusters have been very attractive due to their aesthetic structures and fascinating properties. Different from nanoparticles, each cluster of a macroscopic sample has a well-defined structure with identical composition, size, and shape. As the disadvantages of polydispersity are ruled out, informative structure-property relationships of metal clusters can be established. The formation of a high-nuclearity metal cluster involves the organization of metal ions into a complex entity in an ordered way. To achieve controllable preparation of metal clusters, it is helpful to introduce a directing agent in the formation process of a cluster. To this end, anion templates have been used to direct the formation of high nuclearity clusters. In this Account, the role of anions played in the formation of a variety of silver clusters has been reviewed. Silver ions are positively charged, so anionic species could be utilized to control the formation of silver clusters on the basis of electrostatic interactions, and the size and shape of the resulted clusters can be dictated by the templating anions. In addition, since the anion is an integral component in the silver clusters described, the physical properties of the clusters can be modulated by functional anions. The templating effects of simple inorganic anions and polyoxometales are shown in silver alkynyl clusters and silver thiolate clusters. Intercluster compounds are also described regarding the importance of anions in determining the packing of the ion pairs and making contribution to electron communications between the positive and negative counterparts. The role of the anions is threefold: (a) an anion is advantageous in stabilizing a cluster via balancing local positive charges of the metal cations; (b) an anion template could help control the size and shape of a cluster product; (c) an anion can be a key factor in influencing the function of a cluster through bringing in its intrinsic properties. Properties including electron communication, luminescent thermochromism, single-molecule magnet, and intercluster charge transfer associated with anion-directed silver clusters have been discussed. We intend to attract chemists' attention to the role that anions could play in determining the structures and properties of metal complexes, especially clusters. We hope that this Account will stimulate more efforts in exploiting new role of anions in various metal cluster systems. Anions can do much more than counterions for charge balance, and they should be considered in the design and synthesis of cluster-based functional materials.

[Mn(III)Mn(IV)2Mo14O56](17-): A Mixed-Valence Meso-Polyoxometalate Anion Encapsulated by a 64-Nuclearity Silver Cluster.

A 64-nuclearity silver cluster encapsulating a unique POM anion [Mn(III)Mn(IV)2Mo14O56](17-) has been synthesized. The formation of the templating core performs a reassembly process for increasing nuclearities from {MnMo9} to {Mn3Mo14}. It represents a rare inorganic meso anion containing mixed-valent Mn that is built up by d-{Mn(IV)Mo7} and l-{Mn(IV)Mo7} units connecting together through a {Mn(III)} fragment.

Roles of different forms of lipopolysaccharides in Ralstonia solanacearum pathogenesis.

Lipopolysaccharides (LPS) are critical components for the fitness of most gram-negative bacteria. Ralstonia solanacearum causes a deadly wilting disease in many crops; however, the pathogenic roles of different forms of LPS and their pathways of biogenesis remain unknown. By screening for phage-resistant mutants of R. solanacearum Pss4, whose genome sequence is unavailable, mutants with various types of structural defects in LPS were isolated. Pathogenesis assays of the mutants revealed that production of rough LPS (R-LPS), which does not contain O-polysaccharides, was sufficient to cause necrosis on Nicotiana benthamiana and induce the hypersensitive response on N. tabacum. However, biosynthesis of smooth LPS (S-LPS), which contains O-polysaccharides, was required for bacterial proliferation at infection sites on N. benthamiana leaves and for proliferation and causing wilt on tomato. Complementation tests confirmed the involvement of the previously unidentified cluster RSc2201 to RSc2204 in the formation of R. solanacearum S-LPS. With these data and the availability of the annotated genomic sequence of strain GMI1000, certain loci involved in key steps of R. solanacearum LPS biosynthesis were identified. The strategy of this work could be useful for similar studies in other bacteria without available genome sequences.