AUTS2 disruption causes neuronal differentiation defects in human cerebral organoids through hyperactivation of the WNT/ß-catenin pathway.

Individuals with the Autism Susceptibility Candidate 2 (AUTS2) gene disruptions exhibit symptoms such as intellectual disability, microcephaly, growth retardation, and distinct skeletal and facial differences. The role of AUTS2 in neurodevelopment has been investigated using animal and embryonic stem cell models. However, the precise molecular mechanisms of how AUTS2 influences neurodevelopment, particularly in humans, are not thoroughly understood. Our study employed a 3D human cerebral organoid culture system, in combination with genetic, genomic, cellular, and molecular approaches, to investigate how AUTS2 impacts neurodevelopment through cellular signaling pathways. We used CRISPR/Cas9 technology to create AUTS2-deficient human embryonic stem cells and then generated cerebral organoids with these cells. Our transcriptomic analyses revealed that the absence of AUTS2 in cerebral organoids reduces the populations of cells committed to the neuronal lineage, resulting in an overabundance of cells with a transcription profile resembling that of choroid plexus (ChP) cells. Intriguingly, we found that AUTS2 negatively regulates the WNT/ß-catenin signaling pathway, evidenced by its overactivation in AUTS2-deficient cerebral organoids and in luciferase reporter cells lacking AUTS2. Importantly, treating the AUTS2-deficient cerebral organoids with a WNT inhibitor reversed the overexpression of ChP genes and increased the downregulated neuronal gene expression. This study offers new insights into the role of AUTS2 in neurodevelopment and suggests potential targeted therapies for neurodevelopmental disorders.

Mitochondrial dysfunction and therapeutic perspectives in osteoporosis.

Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass and structural deterioration of bone tissue, resulting in heightened vulnerability to fractures due to increased bone fragility. This condition primarily arises from an imbalance between the processes of bone resorption and formation. Mitochondrial dysfunction has been reported to potentially constitute one of the most crucial mechanisms influencing the pathogenesis of osteoporosis. In essence, mitochondria play a crucial role in maintaining the delicate equilibrium between bone formation and resorption, thereby ensuring optimal skeletal health. Nevertheless, disruption of this delicate balance can arise as a consequence of mitochondrial dysfunction. In dysfunctional mitochondria, the mitochondrial electron transport chain (ETC) becomes uncoupled, resulting in reduced ATP synthesis and increased generation of reactive oxygen species (ROS). Reinforcement of mitochondrial dysfunction is further exacerbated by the accumulation of aberrant mitochondria. In this review, we investigated and analyzed the correlation between mitochondrial dysfunction, encompassing mitochondrial DNA (mtDNA) alterations, oxidative phosphorylation (OXPHOS) impairment, mitophagy dysregulation, defects in mitochondrial biogenesis and dynamics, as well as excessive ROS accumulation, with regards to OP (Figure 1). Furthermore, we explore prospective strategies currently available for modulating mitochondria to ameliorate osteoporosis. Undoubtedly, certain therapeutic strategies still require further investigation to ensure their safety and efficacy as clinical treatments. However, from a mitochondrial perspective, the potential for establishing effective and safe therapeutic approaches for osteoporosis appears promising.

Phosphonylacylation of Alkenes Enabled by Visible-Light-Induced N-Heterocyclic Carbene Catalysis.

Herein, we report the phosphonylacylation of alkenes via visible-light-induced N-heterocyclic carbene (NHC) catalysis to afford a series of γ-ketophosphonates in moderate to good yields. This protocol features mild conditions, free of photocatalyst, and good compatibility of functional groups. The excited Breslow enolate intermediate was proposed to undergo single-electron transfer with oxime phosphonate to generate the corresponding ketyl radical and phosphonyl radical.

Winter is coming: An investigation of vigilant leadership, antecedents, and outcomes.

Within the hierarchical taxonomy of effective leadership, change-oriented leadership stands as a distinct and meaningful metacategory, primarily focusing on promoting change by communicating a compelling vision for the future. However, we consider whether there might be room to broaden the scope of change-oriented leadership by examining more negative-focused leadership behaviors. In this article, we explore the concept of vigilant leadership, which we suggest could be a change-oriented and negative-focused leadership style, and investigate its usefulness as a new leadership construct. In Study 1, we take preliminary steps toward developing a measure of vigilant leadership, employing content adequacy assessment and item response theory analysis. Drawing on the integrative trait-behavioral model of leadership effectiveness (DeRue et al., 2011), we further explore how vigilant leadership is associated with an array of antecedents (i.e., leader characteristics) and leadership outcomes. In Studies 2a and 2b, we present initial findings that leaders high on consideration of future consequences, prevention focus, general self-efficacy, and emotional intelligence might be more inclined to exhibit vigilant leadership. In Study 3, our results suggest that, even after controlling for the effect of visionary leadership (a type of positive-focused change-oriented leadership), vigilant leadership is positively related to follower felt responsibility for change, proactivity, specific proactive work behaviors (taking charge, voice, and problem prevention), teamwork proactivity, and teamwork proficiency. However, it does not seem to relate to follower proficiency, follower adaptivity, teamwork adaptivity, organizational citizenship behavior, positive affect toward the leader, leader-member exchange, or relational identification with the leader. With these preliminary findings, we encourage further discussion and investigation into the potential implications of this emerging construct. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cuproptosis-a potential target for the treatment of osteoporosis.

Osteoporosis is an age-related disease of bone metabolism marked by reduced bone mineral density and impaired bone strength. The disease causes the bones to weaken and break more easily. Osteoclasts participate in bone resorption more than osteoblasts participate in bone formation, disrupting bone homeostasis and leading to osteoporosis. Currently, drug therapy for osteoporosis includes calcium supplements, vitamin D, parathyroid hormone, estrogen, calcitonin, bisphosphates, and other medications. These medications are effective in treating osteoporosis but have side effects. Copper is a necessary trace element in the human body, and studies have shown that it links to the development of osteoporosis. Cuproptosis is a recently proposed new type of cell death. Copper-induced cell death regulates by lipoylated components mediated via mitochondrial ferredoxin 1; that is, copper binds directly to the lipoylated components of the tricarboxylic acid cycle, resulting in lipoylated protein accumulation and subsequent loss of iron-sulfur cluster proteins, leading to proteotoxic stress and eventually cell death. Therapeutic options for tumor disorders include targeting the intracellular toxicity of copper and cuproptosis. The hypoxic environment in bone and the metabolic pathway of glycolysis to provide energy in cells can inhibit cuproptosis, which may promote the survival and proliferation of various cells, including osteoblasts, osteoclasts, effector T cells, and macrophages, thereby mediating the osteoporosis process. As a result, our group tried to explain the relationship between the role of cuproptosis and its essential regulatory genes, as well as the pathological mechanism of osteoporosis and its effects on various cells. This study intends to investigate a new treatment approach for the clinical treatment of osteoporosis that is beneficial to the treatment of osteoporosis.

Distal p-benzylic deuteration via N-heterocyclic carbene catalyzed ring opening of p-cyclopropylbenzaldehydes.

Deuterium incorporation at selective sites of organic compounds has long attracted the interest of the pharmaceutical industry. Here, we present a distal p-benzylic deuteration via N-heterocyclic carbene catalyzed ring-opening of cyclopropylbenzaldehydes with MeOD as the deuterium source. The corresponding 4-alkylbenzoates with high deuterium incorporation at the benzylic position were obtained in good yields. The stable benzylic deuterium remained intact for further chemical transformations.

Bifunctional NHC-Catalyzed Remote Enantioselective Mannich-type Reaction of 5-(Chloromethyl)furfural via Trienolate Intermediates.

N-heterocyclic carbene (NHC)-catalyzed enantioselective Mannich-type reactions of the biomass-derived platform compound 5-(chloromethyl)furfural (CMF) with imines were developed. A series of high-value-added chiral amines were afforded in good to high yields with excellent regio- and enantioselectivities. The bifunctional NHC derived from ʟ-pyroglutamic acid efficiently steered the remote addition of the trienolate intermediate to the imine in a highly stereocontrolled manner. This represents the first enantioselective reaction proceeding via an NHC-bound trienolate intermediate.

Iminoacylation of Alkenes via Photoredox N-Heterocyclic Carbene Catalysis.

The iminoacylation of alkenes via photoredox N-heterocyclic carbene catalysis is developed with the employment of alkene-tethered α-imino-oxy acids and acyl imidazoles. The corresponding substituted 3,4-dihydro-2H-pyrroles were afforded in moderate to good yields with good to high diastereoselectivities in most cases. The reaction involves the 5-exo-trig radical cyclization of an alkene-tethered iminyl radical and the following coupling with a ketyl radical from acyl imidazole under NHC catalysis.

Enantioselective N-Heterocyclic Carbene Catalyzed α-Oxidative Coupling of Enals with Carboxylic Acids Using an Iodine(III) Reagent.

The enantioselective α-oxidative coupling of enals with carboxylic acids was developed via the umpolung of an NHC-bound enolate with an iodine(III) reagent. The corresponding α-acyloxyl-ß,γ-unsaturated esters were afforded in good yields, with high regio- and enantioselectivities. The key step of the reaction involves the formation of enol iodine(III) intermediate from the enolate with iodosobenzene, which changes the polarity of α-carbon of the enal from nucleophilic to electrophilic, and thus facilitates the subsequent addition of carboxylate.

AUTS2 Controls Neuronal Lineage Choice Through a Novel PRC1-Independent Complex and BMP Inhibition.

Despite a prominent risk factor for Neurodevelopmental disorders (NDD), it remains unclear how Autism Susceptibility Candidate 2 (AUTS2) controls the neurodevelopmental program. Our studies investigated the role of AUTS2 in neuronal differentiation and discovered that AUTS2, together with WDR68 and SKI, forms a novel protein complex (AWS) specifically in neuronal progenitors and promotes neuronal differentiation through inhibiting BMP signaling. Genomic and biochemical analyses demonstrated that the AWS complex achieves this effect by recruiting the CUL4 E3 ubiquitin ligase complex to mediate poly-ubiquitination and subsequent proteasomal degradation of phosphorylated SMAD1/5/9. Furthermore, using primary cortical neurons, we observed aberrant BMP signaling and dysregulated expression of neuronal genes upon manipulating the AWS complex, indicating that the AWS-CUL4-BMP axis plays a role in regulating neuronal lineage specification in vivo. Thus, our findings uncover a sophisticated cellular signaling network mobilized by a prominent NDD risk factor, presenting multiple potential therapeutic targets for NDD.

ε-Benzylation via Cooperative Photoredox and N-Heterocyclic Carbene Catalysis.

The ε-benzylation of γ-alkenyl-γ-oxidized enals via dual photoredox and N-heterocyclic carbene catalysis has been developed, affording the corresponding ε-benzyl-α,ß-γ,δ-bisunsaturated esters in moderate to good yields with exclusive regioselectivities. The reaction is proposed via the generation of benzyl radical under photocatalysis, followed by its addition to an NHC-bound trienolate intermediate.

Photoredox cooperative N-heterocyclic carbene/palladium-catalysed alkylacylation of alkenes.

Three-component carboacylation of simple alkenes with readily available reagents is challenging. Transition metal-catalysed intermolecular carboacylation works for alkenes with strained ring or directing groups. Herein, we develop a photoredox cooperative N-heterocyclic carbene/Pd-catalysed alkylacylation of simple alkenes with aldehydes and unactivated alkyl halides to provide ketones in good yields. This multicomponent coupling reaction features a wide scope of alkenes, broad functional group compatibility and free of exogenous photosensitizer or external reductant. In addition, a series of chlorinated cyclopropanes with one or two vicinal quaternary carbons is obtained when chloroform or carbon tetrachloride is used as the alkyl halide. The reaction involves the alkyl radicals from halides and the ketyl radicals from aldehydes under photoredox cooperative N-heterocyclic carbene/Pd catalysis.

Ferroptosis - A new target of osteoporosis.

Osteoporosis is a bone metabolic disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture, leading to enhanced skeletal fragility and susceptibility to fracture. Unbalanced bone remodeling is the primary pathogenetic factor of osteoporosis, in which osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation. Bisphosphonates and calcitonin are among the drugs commonly used to treat osteoporosis, in addition to the bone nutrients vitamin D and calcium supplements. The current treatments effectively prevent further bone loss by inhibiting the excessive activation of osteoclasts, accompanied by various degrees of side effects. Iron, one of the trace elements essential for life activities, has recently been recognized as an independent risk factor for osteoporosis. Abnormal iron metabolism increases the incidence of many bone diseases, especially osteoporosis. Iron metabolism does play a key role in bone homeostasis. Ferroptosis is a novel form of cell death that has been discovered in recent years. Its main features include iron overload and the accumulation of ROS. And lipid peroxidation is the key. There are increasing shreds of evidence that ferroptosis is involved in the occurrence and development of osteoporosis, and its regulation can effectively prevent osteoporosis. Therefore, this review further elucidates the role of ferroptosis in osteoporosis based on the mechanism and its relationship with osteoporosis and provides a new idea for treating osteoporosis.

Targeting STING: From antiviral immunity to treat osteoporosis.

The cGAS-STING signaling pathway can trigger innate immune responses by detecting dsDNA from outside or within the host. In addition, the cGAS-STING signaling pathway has emerged as a critical mediator of the inflammatory response and a new target for inflammatory diseases. STING activation leads to dimerization and translocation to the endoplasmic reticulum Golgi intermediate compartment or Golgi apparatus catalyzed by TBK1, triggers the production of IRF3 and NF-κB and translocates to the nucleus to induce a subsequent interferon response and pro-inflammatory factor production. Osteoporosis is a degenerative bone metabolic disease accompanied by chronic sterile inflammation. Activating the STING/IFN-ß signaling pathway can reduce bone resorption by inhibiting osteoclast differentiation. Conversely, activation of STING/NF-κB leads to the formation of osteoporosis by increasing bone resorption and decreasing bone formation. In addition, activation of STING inhibits the generation of type H vessels with the capacity to osteogenesis, thereby inhibiting bone formation. Here, we outline the mechanism of action of STING and its downstream in osteoporosis and discuss the role of targeting STING in the treatment of osteoporosis, thus providing new ideas for the treatment of osteoporosis.

New type of autocollimator based on the normal tracing method and Risley prisms.

In the present study, we proposed a new type of autocollimator for high-accuracy angular measurement within a large angle range. The new system comprises a traditional autocollimator and Risley prisms, and it employs the normal tracing method to measure the angle. By rotating the Risley prisms, the outgoing beam of the autocollimator can be deflected close to the normal direction of the reflecting mirror and then reflected back to the system by the mirror along the near normal direction to realize normal tracing. Based on the angle measured by the the autocollimator and the rotation angles of Risley prisms, we can calculate the tilt angle of the mirror. Since the beam returns to the system close to the original path, the angle error caused by aberration, optical component processing defects, nonuniform refractive index, and so on, can be ignored. Due to the normal tracing measurement method, theoretically, the angle error is not affected by the working distance. ZEMAX non-sequential simulation shows that the angle error caused by aberration in the new system can be significantly reduced.

Bmi1 Regulates Wnt Signaling in Hematopoietic Stem and Progenitor Cells.

Polycomb group protein Bmi1 is essential for hematopoietic stem cell (HSC) self-renewal and terminal differentiation. However, its target genes in hematopoietic stem and progenitor cells are largely unknown. We performed gene expression profiling assays and found that genes of the Wnt signaling pathway are significantly elevated in Bmi1 null hematopoietic stem and progenitor cells (HSPCs). Bmi1 is associated with several genes of the Wnt signaling pathway in hematopoietic cells. Further, we found that Bmi1 represses Wnt gene expression in HSPCs. Importantly, loss of ß-catenin, which reduces Wnt activation, partially rescues the HSC self-renewal and differentiation defects seen in the Bmi1 null mice. Thus, we have identified Bmi1 as a novel regulator of Wnt signaling pathway in HSPCs. Given that Wnt signaling pathway plays an important role in hematopoiesis, our studies suggest that modulating Wnt signaling may hold potential for enhancing HSC self-renewal, thereby improving the outcomes of HSC transplantation.

Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms.

Polycomb group (PcG) proteins function as vital epigenetic regulators in various biological processes, including pluripotency, development, and carcinogenesis. PcG proteins form multicomponent complexes, and two major types of protein complexes have been identified in mammals to date, Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The PRC1 complexes are composed in a hierarchical manner in which the catalytic core, RING1A/B, exclusively interacts with one of six Polycomb group RING finger (PCGF) proteins. This association with specific PCGF proteins allows for PRC1 to be subdivided into six distinct groups, each with their own unique modes of action arising from the distinct set of associated proteins. Historically, PRC1 was considered to be a transcription repressor that deposited monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1) and compacted local chromatin. More recently, there is increasing evidence that demonstrates the transcription activation role of PRC1. Moreover, studies on the higher-order chromatin structure have revealed a new function for PRC1 in mediating long-range interactions. This provides a different perspective regarding both the transcription activation and repression characteristics of PRC1. This review summarizes new advancements regarding the composition of mammalian PRC1 and accompanying explanations of how diverse PRC1-associated proteins participate in distinct transcription regulation mechanisms.

NHC/Copper-Cocatalyzed [4 + 3] Annulations of Salicylaldehydes with Aziridines for the Synthesis of 1,4-Benzoxazepinones.

N-heterocyclic carbene/copper-cocatalyzed [4 + 3] annulation of salicylaldehydes with aziridines was developed, giving the corresponding 1,4-benzoxazepinones in good yields with exclusive regioselectivity. Copper serves as a Lewis acid to activate the small strained aziridines, and the formation of NHC-salicylaldehyde adduct plays an important role in improving the regioselectivity.

Author Correction: Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Differentiation and Characterization of Neural Progenitors and Neurons from Mouse Embryonic Stem Cells.

We describe the step-by-step procedure for culturing and differentiating mouse embryonic stem cells into neuronal lineages, followed by a series of assays to characterize the differentiated cells. The E14 mouse embryonic stem cells were used to form embryoid bodies through the hanging drop method, and then induced to differentiate into neural progenitor cells by retinoic acid, and finally differentiated into neurons. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunofluorescence experiments revealed that the neural progenitors and neurons exhibit corresponding markers (nestin for neural progenitors and neurofilament for neurons) at day 8 and 12 post-differentiation, respectively. Flow cytometry experiments on an E14 line expressing a Sox1 promoter-driven GFP reporter showed that about 60% of cells at day 8 are GFP positive, indicating the successful differentiation of neural progenitor cells at this stage. Finally, RNA-seq analysis was used to profile the global transcriptomic changes. These methods are useful for analyzing the involvement of specific genes and pathways in regulating the cell identity transition during neuronal differentiation.