Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer.

Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.

Distinct neurofunctional alterations during motivational and hedonic processing of natural and monetary rewards in depression - a neuroimaging meta-analysis.

Reward processing dysfunctions are considered a candidate mechanism underlying anhedonia and apathy in depression. Neuroimaging studies have documented that neurofunctional alterations in mesocorticolimbic circuits may neurally mediate these dysfunctions. However, common and distinct neurofunctional alterations during motivational and hedonic evaluation of monetary and natural rewards in depression have not been systematically examined. Here, we capitalized on pre-registered neuroimaging meta-analyses to (1) establish general reward-related neural alterations in depression, (2) determine common and distinct alterations during the receipt and anticipation of monetary v. natural rewards, and, (3) characterize the differences on the behavioral, network, and molecular level. The pre-registered meta-analysis (https://osf.io/ay3r9) included 633 depressed patients and 644 healthy controls and revealed generally decreased subgenual anterior cingulate cortex and striatal reactivity toward rewards in depression. Subsequent comparative analyses indicated that monetary rewards led to decreased hedonic reactivity in the right ventral caudate while natural rewards led to decreased reactivity in the bilateral putamen in depressed individuals. These regions exhibited distinguishable profiles on the behavioral, network, and molecular level. Further analyses demonstrated that the right thalamus and left putamen showed decreased activation during the anticipation of monetary reward. The present results indicate that distinguishable neurofunctional alterations may neurally mediate reward-processing alterations in depression, in particular, with respect to monetary and natural rewards. Given that natural rewards prevail in everyday life, our findings suggest that reward-type specific interventions are warranted and challenge the generalizability of experimental tasks employing monetary incentives to capture reward dysregulations in everyday life.

Safety and Feasibility of Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy With Calcium-Containing Solutions: A Randomized Controlled Trial.

BACKGROUND: Calcium-free (Ca-free) solutions are theoretically the most ideal for regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT). However, the majority of medical centers in China had to make a compromise of using commercially available calcium-containing (Ca-containing) solutions instead of Ca-free ones due to their scarcity. This study was designed to probe into the potential of Ca-containing solution as a secure and efficient substitution for Ca-free solutions. METHODS: In this prospective, randomized single-center trial, 99 patients scheduled for CRRT were randomly assigned in a 1:1:1 ratio to one of three treatment groups: continuous veno-venous hemodialysis Ca-free dialysate (CVVHD Ca-free) group, continuous veno-venous hemodiafiltration calcium-free dialysate (CVVHDF Ca-free) group, and continuous veno-venous hemodiafiltration Ca-containing dialysate (CVVHDF Ca-containing) group at cardiac intensive care unit (CICU). The primary endpoint was the incidence of metabolic complications. The secondary endpoints included premature termination of treatment, thrombus of filter, and bubble trap after the process. RESULTS: The incidence of citrate accumulation (18.2% vs. 12.1% vs. 21.2%) and metabolic alkalosis (12.1% vs. 0% vs. 9.1%) did not significantly differ among three groups (p > 0.05 for both). The incidence of premature termination was comparable among the groups (18.2% vs. 9.1% vs. 9.1%, p = 0.582). The thrombus level of the filter and bubble trap was similar in the three groups (p > 0.05 for all). CONCLUSIONS: In RCA-CRRT for CICU population, RCA-CVVHDF with Ca-containing solutions and traditional RCA with Ca-free solutions had a comparable safety and feasibility. TRIAL REGISTRATION: ChiCTR2100048238 in the Chinese Clinical Trial Registry.

Dissociable salience and default mode network modulation in generalized anxiety disorder: a connectome-wide association study.

Generalized anxiety disorder (GAD) is a common anxiety disorder experiencing psychological and somatic symptoms. Here, we explored the link between the individual variation in functional connectome and anxiety symptoms, especially psychological and somatic dimensions, which remains unknown. In a sample of 118 GAD patients and matched 85 healthy controls (HCs), we used multivariate distance-based matrix regression to examine the relationship between resting-state functional connectivity (FC) and the severity of anxiety. We identified multiple hub regions belonging to salience network (SN) and default mode network (DMN) where dysconnectivity associated with anxiety symptoms (P < 0.05, false discovery rate [FDR]-corrected). Follow-up analyses revealed that patient's psychological anxiety was dominated by the hyper-connectivity within DMN, whereas the somatic anxiety could be modulated by hyper-connectivity within SN and DMN. Moreover, hypo-connectivity between SN and DMN were related to both anxiety dimensions. Furthermore, GAD patients showed significant network-level FC changes compared with HCs (P < 0.01, FDR-corrected). Finally, we found the connectivity of DMN could predict the individual psychological symptom in an independent GAD sample. Together, our work emphasizes the potential dissociable roles of SN and DMN in the pathophysiology of GAD's anxiety symptoms, which may be crucial in providing a promising neuroimaging biomarker for novel personalized treatment strategies.

Observation and Characterization of Multiple Resonance Modes in a Chiral Helimagnet CrNb3S6.

The chiral helimagnet CrNb3S6 hosts various temperature- and magnetic-field-stabilized chiral soliton lattices (CSLs) and corresponding exotic collective spin resonance modes, which make it an ideal candidate for future magnetic storage/memory and magnon-based information processing. While most studies have focused on characterizing various static spin textures in this chiral helimagnet, its corresponding collective dynamics have rarely been explored. This study systematically investigates the temperature- and magnetic-field-dependent magnetic dynamics of a single crystal of CrNb3S6 using broadband microwave spectroscopy. We observe an optical mode with a temperature-independent mode number in addition to Kittel-like ferromagnetic resonance (FMR) modes in the CSL phase, consistent with the temperature-independent normalized CSL period L(H)/L(0) based on the 1D chiral sine-Gordon model. Furthermore, combining theoretical model fitting and micromagnetic simulation, we provide a detailed phase diagram and temporal-spatial resolution of dynamic modes, which may help to develop high-frequency exchange-coupling-based spintronic devices.

Cofactor-independent C-C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis.

Biosynthesis of atypical angucyclines involves unique oxidative B-ring cleavage and rearrangement reactions, which are catalyzed by AlpJ-family oxygenases, including AlpJ, JadG, and GilOII. Prior investigations established the essential requirement for FADH2/FMNH2 as cofactors when utilizing the quinone intermediate dehydrorabelomycin as a substrate. In this study, we unveil a previously unrecognized facet of these enzymes as cofactor-independent oxygenases when employing the hydroquinone intermediate CR1 as a substrate. The enzymes autonomously drive oxidative ring cleavage and rearrangement reactions of CR1, yielding products identical to those observed in cofactor-dependent reactions of AlpJ-family oxygenases. Furthermore, the AlpJ- and JadG-catalyzed reactions of CR1 could be quenched by superoxide dismutase, supporting a catalytic mechanism wherein the substrate CR1 reductively activates molecular oxygen, generating a substrate radical and the superoxide anion O2 •-. Our findings illuminate a substrate-controlled catalytic mechanism of AlpJ-family oxygenases, expanding the realm of cofactor-independent oxygenases. Notably, AlpJ-family oxygenases stand as a pioneering example of enzymes capable of catalyzing oxidative reactions in either an FADH2/FMNH2-dependent or cofactor-independent manner.

A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigate whether the neonatal liver provides a protumorigenic niche to HB development. APPROACH AND RESULTS: HB development was compared between orthotopic transplantation models established in postnatal day 5 (P5) and 60 (P60) mice (P5Tx and P60Tx models). Single-cell RNA-sequencing (sc-RNAseq) was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. CONCLUSIONS: We found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver that express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout (KO) in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in tumors from patients with metastatic HB, there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with prognosis of patients with HB among pediatric cancers. We demonstrated that the neonatal liver provides a prometastatic niche to HB development through the Cxcl1/Cxcr2 axis.

Negative bias effects during audiovisual emotional processing in major depression disorder.

Aberrant affective neural processing and negative emotional bias are trait-marks of major depression disorders (MDDs). However, most research on biased emotional perception in depression has only focused on unimodal experimental stimuli, the neural basis of potentially biased emotional processing of multimodal inputs remains unclear. Here, we addressed this issue by implementing an audiovisual emotional task during functional MRI scanning sessions with 37 patients with MDD and 37 gender-, age- and education-matched healthy controls. Participants were asked to distinguish laughing and crying sounds while being exposed to faces with different emotional valences as background. We combined general linear model and psychophysiological interaction analyses to identify abnormal local functional activity and integrative processes during audiovisual emotional processing in MDD patients. At the local neural level, MDD patients showed increased bias activity in the ventromedial prefrontal cortex (vmPFC) while listening to negative auditory stimuli and concurrently processing visual facial expressions, along with decreased dorsolateral prefrontal cortex (dlPFC) activity in both the positive and negative visual facial conditions. At the network level, MDD exhibited significantly decreased connectivity in areas involved in automatic emotional processes and voluntary control systems during perception of negative stimuli, including the vmPFC, dlPFC, insula, as well as the subcortical regions of posterior cingulate cortex and striatum. These findings support a multimodal emotion dysregulation hypothesis for MDD by demonstrating that negative bias effects may be facilitated by the excessive ventral bottom-up negative emotional influences along with incapability in dorsal prefrontal top-down control system.

Extrapolating distortion correction with local measurements for space-based multi-module splicing large-format infrared cameras.

Conventional distortion correction methods with the classical models, including radial, decentering, and thin prism distortions and with the interpolation template, depend heavily on the evenly distributed measurement data on the entire focal plane. However, owing to the restricted cubage of the vacuum tank and the large size of the assembled camera, there is no more extra space for the amounted large-format camera to adjust with the 2D turntable during laboratory vacuum experiment, which, accordingly, makes the collected measurement points gathered in just one module of the focal plane and eventually results in poor correction accuracy of the mentioned approaches. Here, in terms of the problems above, an extrapolating distortion correction method with local measurements for space-based multi-module splicing large-format infrared cameras was proposed in this paper. Benefiting from the polynomial model not being affected by the distribution of data, a third-order polynomial model adopted for distortion correction is solved by using local measurements and extrapolated reasonably, which guarantees the global camera calibration. Experimental results show that the mean distortion error can be corrected within 0.5 pixels. This method overcoming the deficiency of local test points can effectively improve the correction accuracy of the large-format camera and provide a new idea for global high-precision calibration of on-orbit payloads based on local measurements.

Integrating Multilevel Functional Characteristics Reveals Aberrant Neural Patterns during Audiovisual Emotional Processing in Depression.

Emotion dysregulation is one of the core features of major depressive disorder (MDD). However, most studies in depression have focused on unimodal emotion processing, whereas emotional perception in daily life is highly dependent on multimodal sensory inputs. Here, we proposed a novel multilevel discriminative framework to identify the altered neural patterns in processing audiovisual emotion in MDD. Seventy-four participants underwent an audiovisual emotional task functional magnetic resonance imaging scanning. Three levels of whole-brain functional features were extracted for each subject, including the task-evoked activation, task-modulated connectivity, combined activation and connectivity. Support vector machine classification and prediction models were built to identify MDD from controls and evaluate clinical relevance. We revealed that complex neural networks including the emotion regulation network (prefrontal areas and limbic-subcortical regions) and the multisensory integration network (lateral temporal cortex and motor areas) had the discriminative power. Moreover, by integrating comprehensive information of local and interactive processes, multilevel models could lead to a substantial increase in classification accuracy and depression severity prediction. Together, we highlight the high representational capacity of machine learning algorithms to characterize the complex network abnormalities associated with emotional regulation and multisensory integration in MDD. These findings provide novel evidence for the neural mechanisms underlying multimodal emotion dysregulation of depression.

Influence of different iron sources on Sb(III) removal from water by active iron-oxidizing bacteria and its mechanism.

Iron-oxidizing bacteria played an important role in the treatment of Sb-containing wastewater. In this study, effect of different iron sources on Sb(III) removal ability by isolated iron-oxidizing bacteria (named as IOB-L) was conducted systemically in batch experiment. Moreover, ferrous lactate and zero-valent iron were chosen as iron sources for IOB-L. The results showed that after inoculation of 2% volume of IOB-L, Sb(III) concentration in water decreased from initial 18 mg/L to 4.1 mg/L at optimal pH of 7.0. There was no reaction between Sb(III) and ferrous lactate, whereas corrosion product of iron can adsorb a certain amount of Sb. When active IOB-L cultivated in ferrous lactate, a better removal rate of Sb(III) can be reached with a longer stagnate phase for bacteria. However, Sb(III) removal ability of IOB-L using zero-valent iron as iron source was lower. SEM-EDS, FTIR, and XPS analysis further indicated that ferrous lactate was oxidized by IOB-L and precipitated as biogenic iron oxides which had strong adsorption ability towards Sb(III), whereas zero-valent iron was not a good iron source.

Deep-Blue Electroluminescence from Phosphine-Stabilized Au3 Triangles and Au3 Ag Pyramids.

The optoelectronic applications of clusters emerged rapidly. Cluster light-emitting diodes (CLED) as representative hold promise as a new generation of displays and lightings. However, as one of the main challenges in electroluminescence (EL) field, until present, no deep-blue CLEDs were reported, due to the strict requirements on excited-state characteristics of clusters. Herein, two phosphine-stabilized Au3 triangle and Au3 Ag pyramid named [O(Audppy)3 ]BF4 and [O(Audppy)3 Ag](BF4 )2 were chosen to demonstrate efficient deep-blue CLEDs. The ligand-incorporated charge transfer transitions of the clusters contribute to both singlet and triplet excited states of the clusters, giving rise to phosphorescence at 460 nm and EL emissions at 436 nm. Based on device engineering, the maximum luminescence beyond 8000 nits and the chromatic coordinates with y <0.1 in deep-blue region verify the competence of CLEDs for high-resolution displays.

Bromodomain-containing protein 4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics.

Although the role of bromodomain-containing protein 4 (BRD4) in ovarian cancer, pancreatic cancer, lymphoma, and many other diseases is well known, its function in cutaneous melanoma is only partially understood. The results of the present study show that the BRD4 inhibitor JQ1 promotes the apoptosis of B16 melanoma cells by altering mitochondrial dynamics, thereby inducing mitochondrial dysfunction and increasing oxidative stress. We found that treatment of B16 cells with different concentrations of JQ1 (125 nmol/L or 250 nmol/L) significantly downregulated the expression of protein subunits involved in mitochondrial respiratory chain complexes I, III, IV, and V, increased reactive oxygen species, induced energy metabolism dysfunction, significantly enhanced apoptosis, and activated the mitochondrial apoptosis pathway. At the same time, JQ1 inhibited the activation of AMP-activated protein kinase, a metabolic energy sensor. In addition, we found that the mRNA and protein levels of mitochondrial dynamin-related protein 1 increased, whereas the levels of mitochondrial fusion protein 1 and optic atrophy protein 1 decreased. Mechanistically, we determined that JQ1 inhibited the expression of c-Myc and altered mitochondrial dynamics, eventually leading to changes in the mitochondrial function, metabolism, and apoptosis of B16 melanoma cells.

Motor Circuit and Superior Temporal Sulcus Activities Linked to Individual Differences in Multisensory Speech Perception.

Integrating multimodal information into a unified perception is a fundamental human capacity. McGurk effect is a remarkable multisensory illusion that demonstrates a percept different from incongruent auditory and visual syllables. However, not all listeners perceive the McGurk illusion to the same degree. The neural basis for individual differences in modulation of multisensory integration and syllabic perception remains largely unclear. To probe the possible involvement of specific neural circuits in individual differences in multisensory speech perception, we first implemented a behavioral experiment to examine the McGurk susceptibility. Then, functional magnetic resonance imaging was performed in 63 participants to measure the brain activity in response to non-McGurk audiovisual syllables. We revealed significant individual variability in McGurk illusion perception. Moreover, we found significant differential activations of the auditory and visual regions and the left Superior temporal sulcus (STS), as well as multiple motor areas between strong and weak McGurk perceivers. Importantly, the individual engagement of the STS and motor areas could specifically predict the behavioral McGurk susceptibility, contrary to the sensory regions. These findings suggest that the distinct multimodal integration in STS as well as coordinated phonemic modulatory processes in motor circuits may serve as a neural substrate for interindividual differences in multisensory speech perception.

On-Orbit Geometric Calibration from the Relative Motion of Stars for Geostationary Cameras.

Affected by the vibrations and thermal shocks during launch and the orbit penetration process, the geometric positioning model of the remote sensing cameras measured on the ground will generate a displacement, affecting the geometric accuracy of imagery and requiring recalibration. Conventional methods adopt the ground control points (GCPs) or stars as references for on-orbit geometric calibration. However, inescapable cloud coverage and discontented extraction algorithms make it extremely difficult to collect sufficient high-precision GCPs for modifying the misalignment of the camera, especially for geostationary satellites. Additionally, the number of the observed stars is very likely to be inadequate for calibrating the relative installations of the camera. In terms of the problems above, we propose a novel on-orbit geometric calibration method using the relative motion of stars for geostationary cameras. First, a geometric calibration model is constructed based on the optical system structure. Then, we analyze the relative motion transformation of the observed stars. The stellar trajectory and the auxiliary ephemeris are used to obtain the corresponding object vector for correcting the associated calibration parameters iteratively. Experimental results evaluated on the data of a geostationary experiment satellite demonstrate that the positioning errors corrected by this proposed method can be within ±2.35 pixels. This approach is able to effectively calibrate the camera and improve the positioning accuracy, which avoids the influence of cloud cover and overcomes the great dependence on the number of the observed stars.

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice.

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.

PFMG1 promotes osteoblast differentiation and prevents osteoporotic bone loss.

Nacre is a widely used mineral medicine that has been reported to have beneficial effects in bone remodeling without an increase in inflammation. Water-soluble nacre matrix has been demonstrated to be responsible for the effect, yet core active ingredients are unknown. Pinctada fucata mantle gene 1 (PFMG1) was first discovered in the mantle tissue of Pinctada fucata. The protein has 2 EF-hands, a calcium-binding domain. PFMG1 protein can affect the growth of calcium carbonate crystals in vitro. Here, we demonstrate that PFMG1 affects cell-cycle distribution and promotes preosteoblast proliferation. PFMG1 accelerates preosteoblast differentiation and extracellular matrix mineralization. During the differentiation process, PFMG1 increases the expression level of osteoblastic marker genes and activates the Erk signaling pathway. PFMG1 also accelerates calcium crystal aggregation in culture medium and suppresses osteoclast formation. Moreover, PFMG1 prevents bone loss caused by ovariectomy. RNA sequencing analysis demonstrated that PFMG1 stimulates genes that are associated with tissue development and ossification, which indicated new genes that function in bone remodeling. Our findings demonstrate the therapeutic potential of PFMG1 from nacre as a novel medicine for osteoporosis.-Li, L., Wang, P., Hu, K., Wang, X., Cai, W., Ai, C., Liu, S., Wang, Z. PFMG1 promotes osteoblast differentiation and prevents osteoporotic bone loss.

Overexpressed SIRT6 attenuates cisplatin-induced acute kidney injury by inhibiting ERK1/2 signaling.

Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase associated with numerous aspects of health and physiology. Overexpression of SIRT6 has emerged as a protector in cardiac tissues against pathologic cardiac hypertrophy. However, the mechanism of this protective effect is not fully understood. Here, both in vivo and in vitro results demonstrated that SIRT6 overexpression can attenuate cisplatin-induced kidney injury in terms of renal dysfunction, inflammation and apoptosis. In addition, SIRT6 knockout aggravated kidney injury caused by cisplatin. We also found that SIRT6 bound to the promoters of ERK1 and ERK2 and deacetylated histone 3 at Lys9 (H3K9) thereby inhibiting ERK1/2 expression. Furthermore, inhibition of ERK1/2 activity eliminated aggravation of kidney injury caused by SIRT6 knock out. Thus, our findings uncover the protective effect of SIRT6 on the kidney and define a new mechanism by which SIRT6 regulates inflammation and apoptosis. This may provide a new therapeutic target for kidney injury under stress.

Metformin promotes the proliferation and differentiation of murine preosteoblast by regulating the expression of sirt6 and oct4.

Osteopenia, osteoporosis and bone salt metabolism disorder are common diseases in the aged and diabetics. From case reports of patients with T2DM, we have observed that metformin can decrease risk of bone fracture and promote bone formation. However, the underlying mechanism of metformin's effect on bone metabolism remains unknown. In our research, we show that metformin can promote proliferation of murine preosteoblast by regulating AMPK-mTORC2 and AKT-mTORC1 signaling axis. Furthermore, we have observed that metformin can promote SIRT6 expression before and during differentiation of murine preosteoblast. The interaction between SIRT6 and NF-κB is highly important in osteoblast differentiation just as the relationship between OPG and RANKL in the process of bone formation. During differentiation, we show that SIRT6 inhibits phosphorylation of NF-κB and that OPG increases while RANKL decrease in HG groups. In addition, ablation of sirt6 in mice causes phosphorylation of NF-κB at high-levels and RANKL increases slightly in femur bone cells. However, other bone formation marker proteins such as RUNX2, OSTERIX and OPG appear at low-levels in sirt6 KO mice. It has been confirmed that downregulation of OCT4 is critical incident in the differentiation of embryonic stem cells. Fortunately, we observe that SIRT6 can suppress OCT4 expression in murine preosteoblast and the expression of OCT4 is at high-level in sirt6 KO mice. Taken together, this study's results illuminate metformin's effect on bone metabolism under HG condition and help to elucidate why metformin can promote bone fracture healing of patients with T2DM.

Ovarian Aging and Osteoporosis.

Osteoporosis is the most common bone metabolic disease with a very high morbidity, and women usually got a higher risk of osteoporosis than men. The high incidence rate of osteoporosis in women was mainly caused by (1) women having fewer skeletons and bone mass, (2) pregnancy consuming a large amount of calcium and other nutrients, and most importantly (3) the cease of estrogen secretion by ovaries after menopause. Along with ovarian aging, the follicle pool gradually declines and the oocyte quality reduced, accompanied with decline in serum estrogen. Estrogen deficiency plays an important role in the pathogenesis of postmenopausal osteoporosis; it is mainly a result of the recognition that estrogen regulates bone remodeling by modulating the production of cytokines and growth factors from bone marrow and bone cells. This review will summarize current knowledge concerning ovarian aging and postmenopause osteoporosis and also discuss clinical treatment and new ideas of drug development for osteoporosis.