Enantioselective Nickel-Electrocatalyzed Reductive Propargylic Carboxylation with CO2.

The exploitation of carbon dioxide (CO2) as a sustainable, plentiful, and harmless C1 source for the catalytic synthesis of enantioenriched carboxylic acids has long been acknowledged as a pivotal task in synthetic chemistry. Herein, we present a current-driven nickel-catalyzed reductive carboxylation reaction with CO2 fixation, facilitating the formation of C(sp3)-C(sp2) bonds by circumventing the handling of moisture-sensitive organometallic reagents. This electroreductive protocol serves as a practical platform, paving the way for the synthesis of enantioenriched propargylic carboxylic acids (up to 98% enantiomeric excess) from racemic propargylic carbonates and CO2. The efficacy of this transformation is exemplified by its successful utilization in the asymmetric total synthesis of (S)-arundic acid, (R)-PIA, (S)-chizhine D, (S)-cochlearin G, and (S,S)-alexidine, thereby underscoring the potential of asymmetric electrosynthesis to achieve complex molecular architectures sustainably.

Observation of giant non-reciprocal charge transport from quantum Hall states in a topological insulator.

Symmetry breaking in quantum materials is of great importance and can lead to non-reciprocal charge transport. Topological insulators provide a unique platform to study non-reciprocal charge transport due to their surface states, especially quantum Hall states under an external magnetic field. Here we report the observation of non-reciprocal charge transport mediated by quantum Hall states in devices composed of the intrinsic topological insulator Sn-Bi1.1Sb0.9Te2S, which is attributed to asymmetric scattering between quantum Hall states and Dirac surface states. A giant non-reciprocal coefficient of up to 2.26 × 105 A-1 is found. Our work not only reveals the properties of non-reciprocal charge transport of quantum Hall states in topological insulators but also paves the way for future electronic devices.

Whole-Exome Sequencing Revealed the Mutational Profiles of Primary Central Nervous System Lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a highly aggressive type of extranodal non-Hodgkin lymphoma, of which approximately 90% of the cases are diffuse large B-cell lymphoma (DLBCL). In recent years, the incidence of PCNSL has significantly increased in women and older men. Although advanced treatments such as high-dose methotrexate (HD-MTX) and targeted agents have been introduced, the prognosis of these patients remains poorer than those with other forms of non-Hodgkin's lymphoma. METHODS: Twelve cases of Chinese PCNSL were analyzed to detect their genetic alterations using whole-exome sequencing (WES). We identified 448 potential somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples. RESULTS: We found that myeloid differentiation factor 88 (MYD88) had the highest mutation frequency, which affected the activity of the nuclear factor-κB (NF-κB) pathway. PCNSL samples with low-density lipoprotein receptor-related protein 1B (LRP1B) mutations had a higher mutation rate than samples with wild-type LRP1B. Polycystic kidney and hepatic disease 1 (PKHD1), the causal gene of autosomal recessive polycystic kidney disease (ARPKD), was identified in 2 PCNSL cases and exhibited missense mutations. Pathway analysis revealed enrichment in pathways associated with central carbon metabolism in cancer, renal cell carcinoma, nicotine addiction, bladder cancer, and long-term depression. CONCLUSIONS: WES revealed significantly mutated genes associated with the molecular mechanisms of PCNSL, which could serve as therapeutic targets to improve patient outcomes.

Large Exchange Bias Effect and Coverage-Dependent Interfacial Coupling in CrI3/MnBi2Te4 van der Waals Heterostructures.

Igniting interface magnetic ordering of magnetic topological insulators by building a van der Waals heterostructure can help to reveal novel quantum states and design functional devices. Here, we observe an interesting exchange bias effect, indicating successful interfacial magnetic coupling, in CrI3/MnBi2Te4 ferromagnetic insulator/antiferromagnetic topological insulator (FMI/AFM-TI) heterostructure devices. The devices originally exhibit a negative exchange bias field, which decays with increasing temperature and is unaffected by the back-gate voltage. When we change the device configuration to be half-covered by CrI3, the exchange bias becomes positive with a very large exchange bias field exceeding 300 mT. Such sensitive manipulation is explained by the competition between the FM and AFM coupling at the interface of CrI3 and MnBi2Te4, pointing to coverage-dependent interfacial magnetic interactions. Our work will facilitate the development of topological and antiferromagnetic devices.

Analysis of Cellular Heterogeneity in Immune Microenvironment of Primary Central Nervous System Lymphoma by Single-Cell Sequencing.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is characterized by a lack of specificity and poor prognosis. Further understanding of the tumor heterogeneity and molecular phenotype of PCNSL is of great significance for improving the diagnosis and treatment of this disease. METHODS: To explore the distinct phenotypic states of PCNSL, transcriptome-wide single-cell RNA sequencing was performed on 34,851 PCNSL cells from patients. The cell types, heterogeneity, and gene subset enrichment of PCNSL were identified. A comparison of the PCNSL cells with 21,250 normal human fetal brain (nHFB) cells was further analyzed to reveal the differences between PCNSL and normal sample. RESULTS: Six cell populations were mainly identified in the PCNSL tissue, including four types of immune cells-B cell, T cell, macrophage and dendritic cell-and two types of stromal cells: oligodendrocyte and meningeal cell. There are significant cellular interactions between B cells and several other cells. Three subpopulations of B cells indicating diffident functions were identified, as well as a small number of plasma cells. Different subtypes of T cells and dendritic cells also showed significant heterogeneity. It should be noted that, compared with normal, the gene expression and immune function of macrophages in PCNSL were significantly downregulated, which may be another important feature of PCNSL in addition to B cell lesions and may be a potential target for PCNSL therapy.

Experimental Observation of the Gate-Controlled Reversal of the Anomalous Hall Effect in the Intrinsic Magnetic Topological Insulator MnBi2Te4 Device.

Magnetic topological insulator, a platform for realizing quantum anomalous Hall effect, axion state, and other novel quantum transport phenomena, has attracted a lot of interest. Recently, it is proposed that MnBi2Te4 is an intrinsic magnetic topological insulator, which may overcome the disadvantages in the magnetic doped topological insulator, such as disorder. Here we report on the gate-reserved anomalous Hall effect (AHE) in the MnBi2Te4 thin film. By tuning the Fermi level using the top/bottom gate, the AHE loop gradually decreases to zero and the sign is reversed. The positive AHE exhibits distinct coercive fields compared with the negative AHE. It reaches a maximum inside the gap of the Dirac cone, and its amplitude exhibits a linear scaling with the longitudinal conductance. The positive AHE is attributed to the competition of the intrinsic Berry curvature and the extrinsic skew scattering. Its gate-controlled switching contributes a scheme for the topological spin field-effect transistors.

Intrinsic magnetic topological insulator phases in the Sb doped MnBi2Te4 bulks and thin flakes.

Magnetic topological insulators (MTIs) offer a combination of topologically nontrivial characteristics and magnetic order and show promise in terms of potentially interesting physical phenomena such as the quantum anomalous Hall (QAH) effect and topological axion insulating states. However, the understanding of their properties and potential applications have been limited due to a lack of suitable candidates for MTIs. Here, we grow two-dimensional single crystals of Mn(SbxBi(1-x))2Te4 bulk and exfoliate them into thin flakes in order to search for intrinsic MTIs. We perform angle-resolved photoemission spectroscopy, low-temperature transport measurements, and first-principles calculations to investigate the band structure, transport properties, and magnetism of this family of materials, as well as the evolution of their topological properties. We find that there exists an optimized MTI zone in the Mn(SbxBi(1-x))2Te4 phase diagram, which could possibly host a high-temperature QAH phase, offering a promising avenue for new device applications.

Ginsenoside-Rb2 inhibits dexamethasone-induced apoptosis through promotion of GPR120 induction in bone marrow-derived mesenchymal stem cells.

Apoptosis of bone marrow-derived mesenchymal stem cells (BMMSCs) is an essential pathogenic factor of osteoporosis. Ginsenoside-Rb2 (Rb2), a 20(S)-protopanaxadiol glycoside extracted from ginseng, is a potent treatment for bone loss, which raises interest regarding the bone metabolism area. In the present study, we found that dose-response Rb2 inhibited high dosage of dexamethasone (Dex)-induced apoptosis in primary murine BMMSCs. Interestingly, Rb2 promoted GPR120 induction, which is the unsaturated long-chain fatty acid receptor. We further confirmed that GPR120-specific ShRNA reversed the inhibition of Rb2 on Dex-induced apoptosis by activating caspase-3 and reducing cell viability. In addition, Rb2 notably increased phosphorylated ERK1/2 levels and Ras kinase activity dependently through the GPR120. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked the Rb2-induced antiapoptotic effect in response to Dex-induced apoptosis. Together, dose-response Rb2 protected BMMSCs against Dex-induced apoptosis dependently by inducing GPR120 promoted Ras-ERK1/2 signaling pathway. Therefore, in the prevalence of the abuse of Dex in the clinic, our findings suggest for the first time that Rb2 is not only a key to understand the link between Chinese medicine and the pathology of osteoporosis but also an underlying target for the treatment of bone complications in the foreseeable future.

Glucocorticoids induce autophagy in rat bone marrow mesenchymal stem cells.

Glucocorticoid­induced osteoporosis (GIOP) is a widespread clinical complication following glucocorticoid therapy. This irreversible damage to bone­forming and ­resorbing cells is essential in the pathogenesis of osteoporosis. Autophagy is a physiological process involved in the regulation of cells and their responses to diverse stimuli, however, the role of autophagy in glucocorticoid­induced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy, immunohistochemistry and western blot analysis detected autophagy in vitro and in GIOP model rats (in vivo). With the addition of the autophagy inhibitor 3­methyladenine, the proliferative ability of BMSCs was further reduced, while the number of apoptotic BMSCs was significantly increased. The data suggests that in response to glucocorticoid administration, induced autophagy aids to maintain proliferation and prevent apoptosis of BMSCs. Thus, it is hypothesized that autophagy may be a novel target in the treatment or prevention of osteoporosis.

Insulin improves osteogenesis of titanium implants under diabetic conditions by inhibiting reactive oxygen species overproduction via the PI3K-Akt pathway.

Clinical evidence indicates that insulin therapy improves implant survival rates in diabetic patients; however, the mechanisms responsible for this effect are unknown. Here, we test if insulin exerts anti-oxidative effects, thereby improving diabetes-associated impaired osteoblast behavior on titanium implants. To test this hypothesis, we cultured primary rabbit osteoblasts in the presence of titanium implants and studied the impact of treatment with normal serum (NS), diabetic serum (DS), DS + insulin, DS + tempol (a superoxide dismutase mimetic), DS + insulin + tempol, and DS + insulin + wortmannin. We analyzed cell function, apoptosis, and reactive oxygen species (ROS) production in osteoblasts following the various treatments. Treatment with DS induced osteoblast dysfunction, evidenced by impaired cell attachment and morphology, decreased cell proliferation and ALP activity, and decreased expression of osteogenesis-related genes. We also observed a significant increase in apoptosis. Importantly, treatment with DS resulted in increased production of ROS in osteoblasts. In contrast, treatment with insulin inhibited ROS production, alleviated cell dysfunction, and decreased apoptosis of osteoblasts on the implants. Scavenging ROS with tempol also attenuated cell dysfunction. Compared to insulin treatment alone, the combination of insulin and tempol failed to further improve osteoblast functional recovery. Moreover, the anti-oxidative and pro-osteogenic effects afforded by insulin were almost completely abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. These results demonstrate, for the first time, that insulin treatment alleviates the impaired osteogenesis of titanium implants under diabetic conditions by inhibiting ROS overproduction via a PI3K/Akt-dependent mechanism. Both the anti-oxidative and metabolic properties of insulin should make it a viable therapeutic option to combat diabetic implant failure.

Dose-dependent effect of estrogen suppresses the osteo-adipogenic transdifferentiation of osteoblasts via canonical Wnt signaling pathway.

Fat infiltration within marrow cavity is one of multitudinous features of estrogen deficiency, which leads to a decline in bone formation functionality. The origin of this fat is unclear, but one possibility is that it is derived from osteoblasts, which transdifferentiate into adipocytes that produce bone marrow fat. We examined the dose-dependent effect of 17ß-estradiol on the ability of MC3T3-E1 cells and murine bone marrow-derived mesenchymal stem cell (BMMSC)-derived osteoblasts to undergo osteo-adipogenic transdifferentiation. We found that 17ß-estradiol significantly increased alkaline phosphatase activity (P<0.05); calcium deposition; and Alp, Col1a1, Runx2, and Ocn expression levels dose-dependently. By contrast, 17ß-estradiol significantly decreased the number and size of lipid droplets, and Fabp4 and PPARγ expression levels during osteo-adipogenic transdifferentiation (P<0.05). Moreover, the expression levels of brown adipocyte markers (Myf5, Elovl3, and Cidea) and undifferentiated adipocyte markers (Dlk1, Gata2, and Wnt10b) were also affected by 17ß-estradiol during osteo-adipogenic transdifferentiation. Western blotting and immunostaining further showed that canonical Wnt signaling can be activated by estrogen to exert its inhibitory effect of osteo-adipogenesis. This is the first study to demonstrate the dose-dependent effect of 17ß-estradiol on the osteo-adipogenic transdifferentiation of MC3T3-E1 cells and BMMSCs likely via canonical Wnt signaling. In summary, our results indicate that osteo-adipogenic transdifferentiation modulated by canonical Wnt signaling pathway in bone metabolism may be a new explanation for the gradually increased bone marrow fat in estrogen-inefficient condition.

Ginsenoside-Rb2 displays anti-osteoporosis effects through reducing oxidative damage and bone-resorbing cytokines during osteogenesis.

Reactive oxygen species (ROS) are a significant pathogenic factor of osteoporosis. Ginsenoside-Rb2 (Rb2), a 20(S)-protopanaxadiol glycoside extracted from ginseng, is a potent antioxidant that generates interest regarding the bone metabolism area. We tested the potential anti-osteoporosis effects of Rb2 and its underlying mechanism in this study. We produced an oxidative damage model induced by hydrogen peroxide (H2O2) in osteoblastic MC3T3-E1 cells to test the essential anti-osteoporosis effects of Rb2in vitro. The results indicated that treatment of 0.1 to 10µM Rb2 promoted the proliferation of MC3T3-E1 cells, improved alkaline phosphatase (ALP) expression, elevated calcium mineralization and mRNA expressions of Alp, Col1a1, osteocalcin (Ocn) and osteopontin (Opn) against oxidative damage induced by H2O2. Importantly, Rb2 reduced the expression levels of receptor activator of nuclear factor kappa-B ligand (RANKL) and IL-6 and inhibited the H2O2-induced production of ROS. The in vivo study indicated that the Rb2 administered for 12weeks partially decreased blood malondialdehyde (MDA) activity and elevated the activity of reduced glutathione (GSH) in ovariectomized (OVX) mice. Moreover, Rb2 improved the micro-architecture of trabecular bones and increased bone mineral density (BMD) of the 4th lumbar vertebrae (L4) and the distal femur. Altogether, these results demonstrated that the potential anti-osteoporosis effects of Rb2 were linked to a reduction of oxidative damage and bone-resorbing cytokines, which suggests that Rb2 might be effective in preventing and alleviating osteoporosis.

Estrogen improves the proliferation and differentiation of hBMSCs derived from postmenopausal osteoporosis through notch signaling pathway.

Estrogen deficiency is the main reason of bone loss, leading to postmenopausal osteoporosis, and estrogen replacement therapy (ERT) has been demonstrated to protect bone loss efficiently. Notch signaling controls proliferation and differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Moreover, imperfect estrogen-responsive elements (EREs) were found in the 5'-untranslated region of Notch1 and Jagged1. Thus, we examined the molecular and biological links between estrogen and the Notch signaling in postmenopausal osteoporosis in vitro. hBMSCs were obtained from healthy women and patients with postmenopausal osteoporosis. Notch signaling molecules were quantified using real-time polymerase chain reaction (real-time PCR) and Western Blot. Luciferase reporter constructs with putative EREs were transfected into hBMSCs and analyzed. hBMSCs were transduced with lentiviral vectors containing human Notch1 intracellular domain (NICD1). We also used N-[N-(3, 5-diflurophenylacetate)-l-alanyl]-(S)-phenylglycine t-butyl ester, a γ-secretase inhibitor, to suppress the Notch signaling. We found that estrogen enhanced the Notch signaling in hBMSCs by promoting the expression of Jagged1. hBMSCs cultured with estrogen resulted in the up-regulation of Notch signaling and increased proliferation and differentiation. Enhanced Notch signaling could enhance the proliferation and differentiation of hBMSCs from patients with postmenopausal osteoporosis (OP-hBMSCs). Our results demonstrated that estrogen preserved bone mass partly by activating the Notch signaling. Because long-term ERT has been associated with several side effects, the Notch signaling could be a potential target for treating postmenopausal osteoporosis.

FFAs-ROS-ERK/P38 pathway plays a key role in adipocyte lipotoxicity on osteoblasts in co-culture.

The accumulation of adipocytes in bone marrow is common in a variety of pathophysiological conditions, including obesity, insulin resistance, type 2 diabetes, and aging. Adipocytes in bone marrow exhibit severe adverse effect on osteoblast differentiation, proliferation, and function. However, the molecular mechanism of adipocytes lipotoxicity on osteoblasts is still far from completely understood. The present study was designed to investigate the signaling pathway responsible for adipocytes lipotoxicity on osteoblasts. Using a co-culture system, we have identified that free fatty acids (FFAs) released by the adipocytes inhibited osteoblasts proliferation and function and induced osteoblasts apoptosis, evidenced by decreased cell viability/proliferation, ALP activity, expression of runt-related transcription factor 2 (RunX2), type I collagen (ColA1) and osteocalcin and alizarin red staining. Dexamethasone (Dex) promoted the inhibitory effect of adipocytes on osteoblasts through stimulating FFAs release. Dex-exacerbated FFAs release from adipocytes contributes to reactive oxygen species (ROS) production. In the co-culture system, the phosphorylation of extracellular signal-regulated kinase (ERK)/P38 was increased and inhibition of ERK/P38 significantly suppressed adipocytes lipotoxicity. FFAs-generated ROS was responsible for adipocytes-induced activation of ERK/P38 signaling. In conclusion, FFAs-ROS-ERK/P38 pathway plays a key role in adipocyte lipotoxicity on osteoblasts in co-culture. The evidence provides new insights into the mechanisms underlying the lipotoxic effect of adipocytes on bone within the marrow microenvironment and prevention of lipotoxicity on bone metabolism.

Protection by salidroside against bone loss via inhibition of oxidative stress and bone-resorbing mediators.

Oxidative stress is a pivotal pathogenic factor for bone loss in mouse model. Salidroside, a phenylpropanoid glycoside extracted from Rhodiola rosea L, exhibits potent antioxidative effects. In the present study, we used an in vitro oxidative stress model induced by hydrogen peroxide (H(2)O(2)) in MC3T3-E1 cells and a murine ovariectomized (OVX) osteoporosis model to investigate the protective effects of salidroside on bone loss and the related mechanisms. We demonstrated that salidroside caused a significant (P<0.05) elevation of cell survival, alkaline phosphatase (ALP) staining and activity, calcium deposition, and the transcriptional expression of Alp, Col1a1 and Osteocalcin (Ocn) in the presence of H(2)O(2). Moreover, salidroside decreased the production of intracellular reactive oxygen species (ROS), and osteoclast differentiation inducing factors such as receptor activator of nuclear factor-kB ligand (RANKL) and IL-6 induced by H(2)O(2). In vivo studies further demonstrated that salidroside supplementation for 3 months caused a decrease in malondialdehyde (MDA) and an increase in reduced glutathione (GSH) concentration in blood of ovariectomized mouse (P<0.05), it also improved trabecular bone microarchitecture and bone mineral density in the fourth lumbar vertebra and distal femur. Our study indicated that the protection provided by salidroside in alleviating bone loss was mediated, at least in part, via inhibition of the release of bone-resorbing mediators and oxidative damage to bone-forming cells, suggesting that salidroside can be used as an effective remedy in the treatment or prevention of osteoporosis.

[Genetic analysis of Mulao nationality using 15 short tandem repeats].

OBJECTIVE: To study the genetic polymorphism of 15 short tandem repeats (STR)(D2S1338, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, D21S11, CSF1PO, TPOX, TH01, vWA, FGA) in Mulao nationality of Guangxi province, and to explore genetic relationship between Mulao nationality and other 10 nationalities. METHODS: The allelic frequencies and the genotype of 15 STR loci were generated from 183 unrelated individuals in Mulao nationality and other 10 nationalities of Guangxi by PCR-STR and genescan. Phylogenetic tree were constracted neighbor-Joining method. RESULTS: There were 136 STR alleles and 422 genotypes in the 15 STR of Mulao nationality, with its allele frequencies ranging from 0.0027 to 0.5243. The average heterozygosity was 0.7632, the accumulative discrimination power was more than 0.999 999 999 9, and the probability of paternity exclusion was more than 0.999 998 469 8. The genetic distances between Mulao nationality and other minority of Guangxi were much closer than those between Mulao nationality and Han nationality and Uighur nationlity. CONCLUSION: The 15 STR loci of Mulao nationality in Guangxi possesses the characteristics of high genetic diversity, except the TPOX locus. They can be employed in group genetic investigation, individual and paternity test in forensic medicine. The genetic distances between Mulao nationality and other minority of Guangxi are more closer than those between Mulao nationality and Han nationality and Uighur nationality.