Leukemia risk assessment of exposure to low-levels of benzene based on the linearized multistage model.

Objectives: To assess leukemia risk in occupational populations exposed to low levels of benzene. Methods: Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m3·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model. Results: The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10-4, respectively; Ptrend < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t-MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10-6. Conclusion: This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m3·year.

Afferent Renal Denervation Attenuates Sympathetic Overactivation From the Paraventricular Nucleus in Spontaneously Hypertensive Rats.

BACKGROUND: The effectiveness of renal denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central renin-angiotensin system (RAS) pathway. METHODS: Ten-week-old spontaneously hypertensive rats (SHR) were subjected to selective afferent renal denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of the paraventricular nucleus (PVN) in SHR. RESULTS: The experimental results show that the ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the PVN, and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. CONCLUSIONS: These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway.

Whether and how will using social media induce social anxiety? The correlational and causal evidence from Chinese society.

Background: Prior literature has well established the relationship between social media use and social anxiety, but little attention has been paid to the underlying mechanisms. Additionally, the causal evidence concerning the effect of social media use on social anxiety is scarce. Objective: Given that, two studies were conducted to examine the effect of social media use on social anxiety and the underlying mechanisms. Methods and results: In Study 1, with 470 undergraduates as participants, we applied the questionnaire survey to investigate the relationship between social media use and social anxiety. The results showed that higher social media use intensity was significantly related to higher social anxiety, and social media use was related to social anxiety via two possible mediation paths: (1) social media use → upward social comparison → social anxiety, (2) and social media use → upward social comparison → self-esteem → social anxiety. In Study 2, with 180 undergraduates as participants, we conducted a lab experiment, in which participants were assigned to the experimental (exposed to the content that undergraduates frequently access on social media) or control (exposed to landscape documentaries) condition, and then measured their upward social comparison, self-esteem and social anxiety. The results showed that participants in the experimental condition reported higher social anxiety than those in the control condition, demonstrating the causality between social media exposure and social anxiety. The subsequent mediation analysis basically replicated the findings of Study 1. That is, upward social comparison played the mediating role between social media exposure and social anxiety, and upward social comparison and self-esteem played the chain-mediating role between them. Conclusion: The current research firstly demonstrated the causality between social media use and social anxiety in Chinese society, and also revealed the mediating mechanisms between them, which would deepen our understanding of how social media use will increase social anxiety.

Cerebral iron deficiency may induce depression through downregulation of the hippocampal glucocorticoid-glucocorticoid receptor signaling pathway.

BACKGROUND: Iron is a trace essential element to sustain the normal neurological function of human. Many researches had reported the involvement of iron deficiency (ID) in neural development and cognitive functions. However, the role of ID in pathogenesis of depression and its underlying mechanism are still unclear. METHODS: In this study, we first used chronic unpredicted mild stress (CUMS) and iron deprivation mouse models to clarify the pathogenesis role of cerebral ID in depression. Then the role of hippocampal glucocorticoid (GC)-glucocorticoid receptor (GR) pathway in cerebral ID induced depression were elucidated in iron deprivation mice and iron deficiency anemia patients. RESULTS: Our results revealed that both CUMS and iron deprivation could induce cerebral ID in mice, and combination of iron deprivation and CUMS could accelerate the onset and aggravate the symptoms of depression in mice. In hippocampus, ID led to neuronal injury and neurogenesis decrease, which might be related to downregulation of GC-GR signaling pathway caused GR dysfunction, thereby inhibiting the negative feedback regulation function of hippocampus on hypothalamic-pituitary-adrenal (HPA) axis. Moreover, the overactivity of HPA axis in iron deprivation mice and iron deficiency anemia patients also confirmed GR dysfunction. LIMITATIONS: Iron deprivation led to food and water intake decrease of mice, which may affect the behavioral test. In addition, we mainly evaluated the role of hippocampal ID in depression, and the number of iron deficiency anemia patients was limited. CONCLUSIONS: Our results identified that cerebral iron homeostasis was a key factor for maintaining mental stability.

[Diagnosis Significance of the Levels of Cytokines IL-6, IL-10 and CXCL-13 in Cerebrospinal Fluid for Central Nervous System Infiltration of Lymphoma].

OBJECTIVE: To evaluate the diagnostic value of the expression levels of cytokines interleukin-6(IL-6), interleukin-10 (IL-10) and chemokine （C-X-C motif） ligand-13 (CXCL-13) in cerebrospinal fluid (CSF) for central nervous system infiltration of lymphoma. METHODS: Forty patients diagnosed as lymphoma or acute lymphoblastic leukemia in General Hospital of Northern Theater Command from July 2020 to July 2021 were collected and recorded their CSF indexes, including pressure, protein, Pandy test, nucleated cell count, glucose and chlorine content in CSF. The levels of cytokines IL-6, IL-10 and CXCL-13 were detected by Enzyme-linked immunosorbent assay. RESULTS: The patients were divided into CNSI (central nervous system infiltration) group and non-CNSI group, the average levels of IL-6, IL-10, CXCL-13 and IL-10/IL-6 ratio in CNSI group were higher than those in non-CNS group, but the difference of IL-10/IL-6 ratio between the two groups was statistically significant (P<0.05). Then the patients were divided into protein elevated(n=14) group and protein normal group(n=26), the levels of IL-6 ï¼» (5.78±2.69) pg/ mlï¼½ and CXCL-13 ï¼»(0.83±0.59) pg/mlï¼½ in protein elevated group were significantly higher than those in the protein normal group ï¼»IL-6: (2.41±1.16) pg/ml; CXCL-13: (0.38±0.18) pg/mlï¼½ (P<0.05). Further analysis of the expression levels of the cytokines in non-CNSI group (n=32), IL-6, IL-10, CXCL-13 level and IL-10/IL-6 ratio in the protein elevated group (n=12) were higher than those in the protein normal group (n=20), but the difference was not statistically significant. CONCLUSION: The levels of IL-6, IL-10 and CXCL-13 in CSF of lymphoma patients with CNS infiltration were higher than those in non-CNS infiltration group, and those in patients with protein elevated group are higher than those in the protein normal group.

Effective-compounds of Jinshui Huanxian formula ameliorates fibroblast activation in pulmonary fibrosis by inhibiting the activation of mTOR signaling.

BACKGROUND: Jinshui Huanxian formula (JHF) ameliorates idiopathic pulmonary fibrosis patients. Active compounds, including icariin, isoliquiritigenin, nobiletin, peimine, and paeoniflorin, deriving from JHF were combined as effective-component compatibility ECC of JHF II (ECC-JHF II), which is an effective therapeutic strategy for pulmonary fibrosis (PF) induced by bleomycin (BLM) in rats. PURPOSE: This study aimed to explore the underlying mechanism of ECC-JHF II on pulmonary fibrosis. METHODS: A model of PF in rats was established through intratracheal instillation of BLM. Pulmonary function, pathological changes, and collagen deposition were examined. The gene and protein expressions in fibroblast activation were detected by quantitative real-time PCR and western blotting respectively. RESULTS: ECC-JHF II significantly improved BLM-induced PF in rats, manifested as decreased collagen deposition, reduced pathological damage and improved pulmonary function. Furthermore, ECC-JHF II inhibited fibroblast activation by reducing the expression of α-smooth muscle actin (α-SMA) and fibronectin. We analyzed the targets of ECC-JHF II and differentially expressed genes (DEGs) of fibroblast activation induced by transforming growth factor-ß1 (TGF-ß1) and found that ECC-JHF II might regulate fibroblast activation by EGFR, PI3K-Akt or mTOR signaling pathway. In vitro experiments, we also found that ECC-JHF II suppressed the mTOR pathway, such as downregulating the phosphorylation levels of p70S6K in fibroblast activation induced by TGF-ß1. After activating mTOR signaling, the inhibition of ECC-JHF II on fibroblast activation was blocked. These results suggested that ECC-JHF II potently ameliorated pulmonary fibrosis in rats and effectively suppressed fibroblast activation by interfering with mTOR signaling. CONCLUSION: We combined transcriptomics with the network analysis to predict the mechanism underlying ECC-JHF II suppression of fibroblast activation. In summary, ECC-JHF II improved BLM-induced pulmonary fibrosis, which might be associated with the suppression of fibroblast activation by inhibiting the mTOR signaling.

My general manager is warmer than department manager: Stereotypes about senior and junior high-power individuals and their influences on spontaneous trait inference.

Introduction: Previous research suggests that high-power (HP) individuals are stereotyped as positive competence but negative warmth. Object: By subdividing HP individuals into junior and senior HP individuals, the current research conducted five studies to examine the warmth perception differences toward senior and junior HP individuals in Confucian culture and the downstream effects on spontaneous trait inference (STI). Method and results: By using different paradigms, Study 1 and 2 found that participants tended to perceive junior HP individuals as negative on the warmth dimension and perceive senior HP individuals as positive on the warmth dimension. The following Study 3 and 4 further found that the warmth perception difference toward senior and junior HP individuals had an influence on STI. Specifically, participants were inclined to make STI from behaviors implying negative warmth traits when behavioral actors were junior HP individuals while they were inclined to make STI from behaviors implying positive warmth traits when behavioral actors were senior HP individuals. Additionally, Study 4 found that perceived social responsibility about HP individuals accounted for the power stereotype effects in STI, the more social responsibility participants perceived about senior HP individuals, the stronger power stereotype effects they showed in STI. The final Study 5 revealed that the different power stereotype effects in STI induced by senior and junior HP actors were observed only in Confucian culture, but not in non-Confucian culture. Conclusion: The present research firstly demonstrated that the warmth perceptions about senior and junior produced different influences on STI in Confucian culture, and also enriched the understanding about the culture-specificity of the stereotype content model.

Effective-component compatibility of Bufei Yishen formula III ameliorated COPD by improving airway epithelial cell senescence by promoting mitophagy via the NRF2/PINK1 pathway.

BACKGROUND: Effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) demonstrates positive effects on stable chronic obstructive pulmonary disease (COPD). PURPOSE: To investigate the mechanisms of ECC-BYF III on COPD rats from the aspect of airway epithelial cell senescence. METHODS: COPD model rats (Sprague-Dawley rat) were treated with ECC-BYF III for 8 weeks, and the efficacy was evaluated. Cigarette smoke extract (CSE)-induced senescence model of airway epithelial cells was treated with ECC-BYF III, and related enzymes and proteins involved in oxidative stress and mitophagy were detected. RESULTS: ECC-BYF III markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including the reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9 levels, increase of the level in total superoxide dismutase (T-SOD), and decease in the p21 level in the airways. Furthermore, ECC-BYF III suppressed p16 and p21 expressions and senescence-associated ß-galactosidase (SA-ß-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF III upregulated mitophagy-related proteins, including the co-localizations of TOM20 and LC3B, PINK1 and PARK2, and improved mitochondrial function by upregulating mitochondrial mitofusin (MFN)2 and reducing dynamin-related protein 1 (DRP1) expression. ECC-BYF III enhanced the activities of T-SOD and GSH-PX by up-regulating NRF2, thus inhibiting oxidative stress. After intervention with NRF2 inhibitor, the regulation effects of ECC-BYF III on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed. CONCLUSIONS: ECC-BYF III exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through the activation of NRF2 signaling.

PDCL2 is essential for spermiogenesis and male fertility in mice.

Patients with teratozoospermia exhibit low phosducin-like protein (Pdcl2) expression. As a member of the phosducin family, chaperonin-related Pdcl2, a germline-specific gene, may be involved in germ cell protein folding. Given that PDCL2 is highly conserved in evolution, it may be indispensable for mammalian spermiogenesis; however, the function of PDCL2 in higher mammalian species remains unknown. To determine the role of PDCL2 in male fertility, we generated Pdcl2 knockout mice using CRISPR/Cas9. Our results revealed that Pdcl2 heterozygous (Pdcl2+/-) male mice were normal, but male Pdcl2-null (Pdcl2-/-) mice were infertile. Accordingly, Pdcl2-/- male mice exhibited lower testis weight, epididymis weight, and sperm number than Pdcl2+/+ mice. Moreover, Pdcl2-/- mice displayed malformed and immotile sperm. Apoptotic cells were significantly enhanced in Pdcl2-/- testes and epididymis when compared with those in wild-type mice. Mechanistically, PDCL2 can interact with the CCT complex, and dysfunction in this complex might lead to infertility in Pdcl2-/- male mice. Collectively, these findings confirm that Pdcl2 knockout leads to male infertility in mice and that PDCL2 may function as a chaperone to promote protein folding during spermiogenesis.

Global mapping of GalNAc-T isoform-specificities and O-glycosylation site-occupancy in a tissue-forming human cell line.

Mucin-type-O-glycosylation on proteins is integrally involved in human health and disease and is coordinated by an enzyme family of 20 N-acetylgalactosaminyltransferases (GalNAc-Ts). Detailed knowledge on the biological effects of site-specific O-glycosylation is limited due to lack of information on specific glycosylation enzyme activities and O-glycosylation site-occupancies. Here we present a systematic analysis of the isoform-specific targets of all GalNAc-Ts expressed within a tissue-forming human skin cell line, and demonstrate biologically significant effects of O-glycan initiation on epithelial formation. We find over 300 unique glycosylation sites across a diverse set of proteins specifically regulated by one of the GalNAc-T isoforms, consistent with their impact on the tissue phenotypes. Notably, we discover a high variability in the O-glycosylation site-occupancy of 70 glycosylated regions of secreted proteins. These findings revisit the relevance of individual O-glycosylation sites in the proteome, and provide an approach to establish which sites drive biological functions.

Synthesis of Tryptamines from Radical Cyclization of 2-Iodoaryl Allenyl Amines and Coupling with 2-Azallyls.

An efficient synthesis of tryptamines is developed. Indole structures were constructed using 2-iodoaryl allenyl amines as electron acceptors and radical cyclization precursors. Radical-radical coupling of indolyl methyl radicals and azaallyl radicals led to the tryptamine derivatives. The utility and versatility of this method are showcased by the synthesis of 22 examples of tryptamines in ≤88% yield. In each case, indole formation is accompanied by in situ removal of the Boc protecting group.

AgNPs Aggravated Hepatic Steatosis, Inflammation, Oxidative Stress, and Epigenetic Changes in Mice With NAFLD Induced by HFD.

The recent development of silver nanoparticles (AgNPs) has sparked increased interest in biomedical and pharmaceutical applications, leading to the possibility of human exposure. The liver is the primary target organ in the metabolism and transport of nanoparticles. Non-alcoholic fatty liver disease (NAFLD) is the most common and leading cause of hepatic metabolic syndrome with approximately 15% of patients will develop into non-alcoholic steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Thus, the potential hepatotoxicity of AgNPs on NAFLD development and progression should be of great concern. Herein, we explored the potential hepatic effect of a single intravenously injected dose of 0.5, 2.5, and 12.5 mg/kg BW on the liver function of high-fat-diet (HFD)-fed mice for 7 days. AgNP treatment increased serum levels of alanine aminotransferase, aspartate transaminase, triglycerides and cholesterols, the number of lipid droplets, and the contents of triglycerides and cholesterols in NAFLD mice livers compared to HFD-fed mice. The mechanism of AgNP-induced worsen hepatotoxicity in mice is associated with hyperactivation of SREBP-1c-mediated de novo lipogenesis and liver inflammation. Additionally, HFD-fed mice treated with AgNPs had significantly higher oxidative damage and lower global DNA methylation and DNA hydroxymethylation than NAFLD mice. This study suggests that AgNP treatment exacerbated HFD-induced hepatic steatosis, liver inflammation, oxidative stress, and epigenetic changes in mice, which is relevant to the risk of AgNP exposure on NAFLD development and progression.

More Power, More Warmth: The Enhancing Effect of Power on the Perceived Warmth About High-Power Individuals Under Chinese Culture.

Previous literature concerning power stereotypes demonstrates that compared to low-power (LP) individuals, high-power (HP) individuals tend to be perceived as having positive competence but negative warmth. Based on previous research, the current research further classified HP into senior and junior HP and mainly compared the perceived warmth between senior and junior HP individuals in Chinese culture. By classifying power into HP and LP, the pilot study employed the trait-rating task to replicate the results of previous research. In Study 1, we classified HP into senior and junior HP and revealed that participants indicated more positive warmth evaluations for senior HP individuals than for junior HP individuals. We named this "more power, more warmth" effect the MPMW effect. Further investigation demonstrated that the MPMW effect was more likely to emerge for participants with high Confucianism identification (Study 2a), for Chinese participants rather than Western participants (Study 2b), or when the knowledge of Confucianism was accessible in a given situation (Study 3). The present research firstly demonstrated that the contents of power stereotypes may partially display culture-specific characteristics in Chinese culture. The continuous classification approach to power provided a novel insight for future power research.

Responsible Leadership Effect on Career Success: The Role of Work Engagement and Self-Enhancement Motives in the Education Sector.

Using social information processing theory, our study investigates the effect of responsible leadership on employee career success via work engagement. The model also examines whether self-enhancement motives moderate the aforementioned mediating linkages. In three waves, data were collected from employees in the education sector. Macro PROCESS was used to assess the hypotheses. According to the findings, responsible leadership boosts employee work engagement, which leads to career success. The results also suggest that responsible leadership has a stronger positive effect on work engagement among individuals high on self-enhancement motives. There is no evidence in the educational literature about the underlying process through which a responsible leadership impacts employee success. Our research addresses this gap by suggesting work engagement as a mediator of the effect of responsible leadership on individuals' career success at various degrees of self-enhancement motives.

α-Branched amines through radical coupling with 2-azaallyl anions, redox active esters and alkenes.

α-Branched amines are fundamental building blocks in a variety of natural products and pharmaceuticals. Herein is reported a unique cascade reaction that enables the preparation of α-branched amines bearing aryl or alkyl groups at the ß- or γ-positions. The cascade is initiated by reduction of redox active esters to alkyl radicals. The resulting alkyl radicals are trapped by styrene derivatives, leading to benzylic radicals. The persistent 2-azaallyl radicals and benzylic radicals are proposed to undergo a radical-radical coupling leading to functionalized amine products. Evidence is provided that the role of the nickel catalyst is to promote formation of the alkyl radical from the redox active ester and not promote the C-C bond formation. The synthetic method introduced herein tolerates a variety of imines and redox active esters, allowing for efficient construction of amine building blocks.

Effects of Exercise Training on PPARß/δ Expression in Skeletal Muscle of Rats with Spontaneous Hypertension.

PURPOSE: This study aimed to identify the relationship and mechanism between skeletal muscle peroxisome proliferator-activated receptor ß/δ (PPARß/δ) and spontaneous hypertension. METHODS: Rats were divided into four groups ( n = 10): spontaneous hypertensive rats exercise group (SHR-E), spontaneous hypertensive rats sedentary group (SHR-S), Wistar-Kyoto control rats exercise group (WKY-E), and Wistar-Kyoto control rats sedentary group (WKY-S). Although the sedentary groups were placed on the treadmill without moving during the training sessions, the exercise groups were forced to run on a treadmill for 8 wk, 1 h·d -1 , 5 d·wk -1 . After training, the density and area of gastrocnemius microvessels were observed. PPARß/δ, vascular endothelial growth factor A (VEGFA), superoxide dismutase 2 (SOD-2), and nitric oxide synthase in gastrocnemius were measured by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. RESULTS: Except the sixth week of age, the systolic blood pressure of SHR-S was significantly higher than that of WKY-S at all time periods. Exercise significantly reduced systolic blood pressure in SHR rats. Compared with the SHR-S group, the WKY-S group had significantly higher PPARß/δ protein level and density of skeletal muscle microvessels. Eight weeks of exercise increased the PPARß/δ, SOD-2, VEGFA, and microvessel density and area in the skeletal muscle of SHR. CONCLUSIONS: Exercise training promoted PPARß/δ mRNA and protein-level expression of PPARß/δ, SOD-2 and VEGFA in skeletal muscle, thus increasing the density and area of skeletal muscle blood vessels. These regulations contribute to the reduction of peripheral vascular resistance. This may be a potential mechanism of exercise to reduce blood pressure.

Super-Electron-Donor 2-Azaallyl Anions Enable Construction of Isoquinolines.

Herein is introduced the application of "super-electron-donor"(SED) 2-azaallyl anions in a tandem reduction/radical cyclization/radical coupling/aromatization protocol that enables the rapid construction of isoquinolines. The value of this transition-metal-free method is highlighted by the wide range of isoquinoline ethyl amines prepared with good functional group tolerance and yields. An operationally simple gram scale synthesis is also conducted, confirming the scalability.

Effective-compound combination inhibits the M2-like polarization of macrophages and attenuates the development of pulmonary fibrosis by increasing autophagy through mTOR signaling.

BACKGROUND AND PURPOSE: The M2 polarization of macrophages substantially contributes to the progression of pulmonary fibrosis (PF). Effective-compound combination (ECC), which is composed of isoliquiritigenin, icariin, nobiletin, peimine, and paeoniflorin, ameliorated bleomycin-induced PF in rats. Hence, we investigated the anti-PF mechanism of ECC with a focus on the suppression of M2 polarization in macrophages in vivo and in vitro. METHODS: The PF rat model was generated via the intratracheal instillation of bleomycin. Histological changes, M2 macrophages, and profibrotic mediators were detected. The M2 polarization model was generated by incubating macrophages with IL-4. Quantitative PCR and Western blotting were used to measure mRNA and protein levels, respectively. RESULTS: ECC attenuated bleomycin-induced PF in rats, which might be associated with reduced macrophage infiltration, M2 polarization, and profibrotic mediator expression. Furthermore, ECC significantly suppressed M2 polarization in IL-4-treated macrophages, which was accompanied by the upregulation of autophagy. An autophagy inhibitor abrogated the inhibitory effect of ECC on M2 polarization. In addition, ECC decreased the levels of p-p70S6K/p-4EBP and p-AKT473/p-GSK3ß, which are critical regulators of autophagy. CONCLUSION: ECC can ameliorate PF, which might be associated with the inhibition of M2 polarization through the promotion of autophagy via mTOR signaling suppression.

Dual Photoredox/Nickel-Promoted Alkylation of Heteroaryl Halides with Redox-Active Esters.

Herein a method for the radical alkylation of heteroaryl halides that relies upon the combination of photoredox and nickel catalysis is described. The use of aliphatic N-(acyloxy)phthalimides as redox-active esters affords primary and secondary radicals for the decarboxylative dual cross-coupling with pyrimidine and pyridine heteroaryl chlorides, bromides, and iodides. The method provides an additional synthetic tool for the incorporation of medicinally relevant heterocyclic motifs.

Nickel-catalyzed enantioselective vinylation of aryl 2-azaallyl anions.

A unique enantioselective nickel-catalyzed vinylation of 2-azaallyl anions is advanced for the first time. This method affords diverse vinyl aryl methyl amines with high enantioselectivities, which are frequently occurring scaffolds in natural products and medications. This C-H functionalization method can also be extended to the synthesis of enantioenriched 1,3-diamine derivatives by employing suitably elaborated vinyl bromides. Key to the success of this process is the identification of a Ni/chiraphos catalyst system and a less reducing 2-azaallyl anion, all of which favor an anionic vinylation route over a background radical reaction. A telescoped gram scale synthesis and a product derivatization study confirmed the scalability and synthetic potential of this method.