SIRT1 maintains bone homeostasis by regulating osteoblast glycolysis through GOT1.

The silent information regulator T1 (SIRT1) is linked to longevity and is a crucial mediator of osteoblast function. We investigated the direct role of Sirt1 during bone modeling and remodeling stages in vivo using Tamoxifen-inducible osteoblast-specific Sirt1 conditional knockout (cKO) mice. cKO mice exhibited lower trabecular and cortical bone mass in the distal femur. These phenotypes were coupled with lower bone formation and bone resorption. Metabolomics analysis revealed that the metabolites involved in glycolysis were significantly decreased in cKO mice. Further analysis of the quantitative acetylome revealed 11 proteins with upregulated acetylation levels in both the femur and calvaria of cKO mice. Cross-analysis identified four proteins with the same upregulated lysine acetylation site in both the femur and calvaria of cKO mice. A combined analysis of the metabolome and acetylome, as well as immunoprecipitation, gene knockout, and site-mutation experiments, revealed that Sirt1 deletion inhibited glycolysis by directly binding to and increasing the acetylation level of Glutamine oxaloacetic transaminase 1 (GOT1). In conclusion, our study suggested that Sirt1 played a crucial role in regulating osteoblast metabolism to maintain bone homeostasis through its deacetylase activity on GOT1. These findings provided a novel insight into the potential targeting of osteoblast metabolism for the treatment of bone-related diseases.

Effective Reduction of CO2 with Aromatic Amines into N-Formamides Triggered by Noble-Free Metal-Organic Framework Catalysts Under Mild Conditions.

The reductive transformation of carbon dioxide (CO2) into high-valued N­formamides matches well with the atom economy and the sustainable development intention. Nevertheless, developing a noble-free metal catalyst under mild reaction conditions is desirable and challenging. Herein, a caged metal-organic framework (MOFs) [H2N(CH3)2]2{[Ni3(µ3-O)(XN)(BDC)3]·6DMF}n (1) (XN = 6″-(pyridin-4-yl)-4,2″:4″,4″'-terpyridine), H2BDC = terephthalic acid) is harvested, presenting high thermal and chemical stabilities. Catalytic investigation reveals that 1 as a renewable noble-free MOFs catalyst can catalyze the CO2 reduction conversion with aromatic amines tolerated by broad functional groups at least ten times, resulting in various formamides in excellent yields and selectivity under the mildest reaction system (room temperature and 1 bar CO2). Density functional theory (DFT) theoretical studies disclose the applicable reaction path, in which the CO2 hydrosilylation process is initiated by the [Ni3] cluster interaction with CO2 via η2-C, O coordination mode. This work may open up an avenue to seek high-efficiency noble-free catalysts in CO2 chemical reduction into high value-added chemicals.

High-fat diet consumption promotes adolescent neurobehavioral abnormalities and hippocampal structural alterations via microglial overactivation accompanied by an elevated serum free fatty acid concentration.

Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders.

Hyaluronic Acid Unveiled: Exploring the Nanomechanics and Water Retention Properties at the Single-Molecule Level.

Hyaluronic acid (HA), a vital glycosaminoglycan in living organisms, possesses remarkable mechanical and viscoelastic properties that have garnered significant attention in therapeutic, biomedical, and cosmetic applications. However, a comprehensive picture of the physicochemical and biocharacterization of HA at the single-molecule level remains elusive. In this work, atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) and molecular dynamics (MD) simulation were used to investigate the nanomechanics and water retention properties of HA at the single-molecule level. The present study aims to unravel the intricate details of the influence of molecular structure on HA behavior and shed light on its unique attributes. According to the force measurements, the energy used to stretch a HA chain in water is 8.45 kJ/mol, significantly surpassing that of Curdlan (3.45 kJ/mol) and chitin (2.23 kJ/mol), both of which possess molecular structures partially similar to that of HA. Intriguingly, the strength of the intrachain interaction of HA (5.54 kJ/mol) was considerably weaker compared to Curdlan (11.06 kJ/mol) and chitin (or cellulose, 10.76 kJ/mol). This result indicates that HA exhibits a preference for interacting with water rather than with itself, thereby showing enhanced water affinity. Moreover, the force measurements demonstrated that changing the glycosidic bond from ß-(1-3) (Curdlan) or ß-(1-4) (chitin or cellulose) to ß-(1-3) + ß-(1-4) (HA) resulted in polysaccharides displaying improved water affinity and more extended conformation. These conclusions were further verified by molecular dynamics (MD) simulations. Overall, our work sheds new light on the nanomechanics and water retention properties of HA at the single-molecule level, offering valuable insights for future research in this field.

Ultrasensitive Eu-Based MOF Luminescence Sensor for Clenbuterol Visible Recognition.

Clenbuterol (CLB) as an illegal feed additive may cause a great security risk to food safety. However, convenient and efficient detection means for CLB in practical application remain a formidable challenge. Herein, a stable Eu-based organic framework {[H2N(CH3)2]2[Eu2(ttca)2]·H2O}n (compound 1) (H4ttca = [1,1':2',1″-terphenyl]-4,4',4″,5'-tetracarboxylic acid) has been harvested, exhibiting excellent chemical stability and thermal stability. Luminescence investigation reveals that compound 1 can sensitively and selectively detect CLB without being affected by different components from simulated serum and urine (limit detection: 22.7 nM). Furthermore, sensor 1 can also be applicable to CLB recognition in real swine feeds, presenting excellent anti-interference performance. The good cyclicity of compound 1 endows CLB determination with many advantages: low cost, high stability, and simplicity. Importantly, in view of the indication of the luminescence color (red to blue), test membranes were fabricated and employed for convenient and fast CLB detection, providing a valuable scheme for the visual monitoring of CLB in meat products. This work enriches rare earth metal compounds and luminescence sensor portfolios and breaks the concentration record (nM) for detecting CLB compared with reported complex materials, providing an effective monitoring platform for CLB visually.

Adult mice with noise-induced hearing loss exhibited temporal ordering memory deficits accompanied by microglia-associated neuroplastic changes in the medial prefrontal cortex.

Acquired peripheral hearing loss in midlife is considered the primary modifiable risk factor for dementia, while the underlying pathological mechanism remains poorly understood. Excessive noise exposure is the most common cause of acquired peripheral hearing loss in modern society. This study was designed to investigate the impact of noise-induced hearing loss (NIHL) on cognition, with a focus on the medial prefrontal cortex (mPFC), a brain region that is involved in both auditory and cognitive processes and is highly affected in patients with cognitive impairment. Adult C57BL/6 J mice were randomly assigned to a control group and seven noise groups: 0HPN, 12HPN, 1DPN, 3DPN, 7DPN, 14DPN, and 28DPN, which were exposed to broadband noise at a 123 dB sound pressure level (SPL) for 2 h and sacrificed immediately (0 h), 12 h, or 1, 3, 7, 14, or 28 days post-noise exposure (HPN, DPN), respectively. Hearing assessment, behavioral tests, and neuromorphological studies in the mPFC were performed in control and 28DPN mice. All experimental animals were included in the time-course analysis of serum corticosterone (CORT) levels and mPFC microglial morphology. The results illustrated that noise exposure induced early-onset transient serum CORT elevation and permanent moderate-to-severe hearing loss in mice. 28DPN mice, in which permanent NIHL has been verified, exhibited impaired performance in temporal order object recognition tasks concomitant with reduced structural complexity of mPFC pyramidal neurons. The time-course immunohistochemical analysis in the mPFC revealed significantly higher morphological microglial activation at 14 and 28 DPN, preceded by a remarkably higher amount of microglial engulfed postsynaptic marker PSD95 at 7 DPN. Additionally, lipid accumulation in microglia was observed in 7DPN, 14DPN and 28DPN mice, suggesting a driving role of lipid handling deficits following excessive phagocytosis of synaptic elements in delayed and sustained microglial abnormalities. These findings provide fundamentally novel information concerning mPFC-related cognitive impairment in mice with NIHL and empirical evidence suggesting the involvement of microglial malfunction in the mPFC neurodegenerative consequences of NIHL.

Ablation of myeloid discoidin domain receptor 2 exacerbates arthritis and high fat diet induced inflammation.

Chronic systemic inflammation leads to sever disorders and diseases. It is of great importance to explore novel target for effective treatment. Discoidin domain receptor 2 (Ddr2) is a member of receptor tyrosine kinase (RTK) family and is implicated in skeletal and fat hemostasis. However, the role of Ddr2 in myeloid cells remains obscure. In this study, we conditionally deleted Ddr2 in myeloid lineage cells to generate cKO mice to investigate the role of Ddr2 in myeloid lineage cells. We found that cKO mice exhibited more severe inflammation both in collagen antibody-induced arthritis (CAIA) and high-fat diet (HFD)-induced obesity, indicating the protective role of Ddr2 against inflammation. Mechanistically, Ddr2 promotes macrophage repolarization from the M1 to M2 phenotype, and protect against systemic inflammation. Our study reveals for the first time that Ddr2 modulates macrophage repolarization and plays critical roles in macrophage-mediated inflammation, providing potential target for the intervention of inflammation and related diseases.

Surface Spin Enhanced High Stable NiCo2 S4 for Energy-Saving Production of H2 from Water/Methanol Coelectrolysis at High Current Density.

Nickel based materials are promising electrocatalysts to produce hydrogen from water in alkaline media. However, the stability is of great challenge, limiting its practical material functions. Herein, a new technique for electro-deposition flower-like NiCo2 S4 nanosheets on carbon-cloth (CC@NiCo2 S4 ) is proposed for energy-saving production of H2 from water/methanol coelectrolysis at high current density by constructing array architectures and regulating surface magnetism. The optimized and fine-tuned magnetism on the surface of the electrochemical in situ grown CC@NiCo2 S4 nanosheet array result in (0 1 -1) surface universally exposed, high catalytic activity for methanol electrooxidation, and long-term stability at high current density. X-ray photoelectron spectroscopy in combination of density functional theory calculations confirm the valence electron states and spin of d electrons for the surface of NiCo2 S4 , which enhance the surface stability of catalysts. This technology may be utilized to alter the surface magnetism and increase the stability of Ni-based electrocatalytic materials in general.

Simultaneous bilateral traumatic clavicle fractures: incidence, characteristics, and surgical outcomes.

BACKGROUND: Although clavicle fractures are common injuries in adults, simultaneous bilateral clavicle fractures are rarely reported. The present report describes 13 patients with simultaneous bilateral traumatic clavicle fractures who were treated with surgical management and followed for more than 12 months postoperatively. METHODS: This retrospective chart review involved skeletally mature patients with traumatic clavicle injuries. Patients with bilateral clavicle fractures who were followed up for at least 12 months after surgery were included. Data regarding the patients' demographics, injury characteristics, fracture classification, comorbidities, concomitant injuries, and treatment strategies were collected. Each displaced fracture was managed with open reduction and internal fixation. Postoperative follow-up included radiographs for assessment of bone union; calculation of the Constant-Murley score for shoulder function; administration of the Disability of the Arm, Shoulder, and Hand questionnaire for upper limb function; determination of the visual analogue scale score for pain; and assessment of complications. RESULTS: From October 2013 to November 2021, 15 patients (10 men, 5 women) were diagnosed with bilateral clavicle fractures among 1542 patients with clavicle injuries (overall incidence of 1.0%). Of these 15 patients, this study included 13 patients (8 men, 5 women; mean age, 38.3 ± 15.3 years) who were followed up for more than 12 months postoperatively. Among the 13 patients, 10 (77.0%) had associated concomitant injuries, and 25 sides were fixed with internal plate fixation. After a follow-up period of 29.9 ± 28.5 months, all fractures achieved bone healing. Eleven patients attained excellent shoulder function on both sides and returned to their pre-injury daily activities, and the remaining two patients had unilateral shoulder dysfunction. No complications occurred. CONCLUSIONS: Bilateral clavicle fractures are extremely rare and associated with polytrauma. Open reduction and internal fixation is recommended for such patients, especially those with severe chest injuries, because osteosynthesis of the clavicle can improve respiratory function and reduce the duration of functional disability.

Treatment of bipolar clavicle injury with internal plating: a case series and literature review.

BACKGROUND: Bipolar clavicle injury is a rare injury involving any combination of dislocation and/or fracture at both ends of the clavicle. Most reports of bipolar clavicle injury have been based on a single case, and treatment of this injury remains controversial. The present study was performed to evaluate the efficacy of surgical management with internal plating for bipolar clavicle injuries. METHODS: We performed internal plating to treat seven consecutive bipolar clavicle injuries with different injury patterns from May 2013 to June 2021. A clavicle hook plate was used for five sternoclavicular joint injuries (including a revision surgery) and three acromioclavicular joint dislocations, a T plate was used for one sternoclavicular joint injury, and an anatomic plate was used for one distal clavicle fracture. At follow-up, radiographs were assessed for bone alignment, joint congruity, fracture union or malunion, and implant failure or migration. Clinical evaluation included determination of the Disability of the Arm, Shoulder, and Hand (DASH) score; Constant-Murley score; visual analog scale (VAS) score; and complications. RESULTS: The patients were regularly followed up after the operation, and functional parameters were assessed over time. At a mean follow-up of 28.1 ± 22.0 months, each fracture had solid bone union, and each dislocation showed no sign of recurrent instability. The mean shoulder forward flexion was 159.3° ± 7.9°, and the mean DASH score was 8.8 ± 5.1. The mean Constant-Murley score was 88.9 ± 7.9, with six cases assessed as excellent and one case assessed as good. The mean VAS score was 1.0 ± 1.5, and the mean patient satisfaction score was 9.3 ± 0.8. No complications occurred, and each patient was able to resume their preinjury daily activity and was highly satisfied with their treatment. CONCLUSIONS: In the present study, internal plating for bipolar clavicle injury allowed early mobilization and resulted in good joint function. We recommend fixation of the more severely affected side first because the other side may be passively reduced and acquire stability once the more severely affected side has been fixed. Internal fixation of the other end may therefore be unnecessary unless residual instability exists.

Effects of Prolonged High-Fat Diet Consumption Starting at Different Ages on Behavioral Parameters and Hippocampal Neuroplasticity in Male Mice.

BACKGROUND: The overconsumption of a high-fat diet (HFD) has been repeatedly blamed as being a possible contributor to the global prevalence of emotional problems in modern society. Our group recently demonstrated the deleterious effect of a chronic HFD throughout adulthood on both emotional behavior and neuroplasticity markers in mice. As a heightened preference for palatable HFDs from the time of the juvenile period (when the brain is particularly vulnerable to environmental insults) is universal among populations around the world, a comparison of the consequences of chronic HFDs starting from juveniles or adults will assist in obtaining better knowledge of the impact that chronic HFDs have on mental health, thus potentially leading to the discovery of more effective strategies for reducing the incidence of psychiatric disorders. METHODS: In the present study, male C57BL/6J mice with an initial age of 4 weeks (IA-4 W) or 8 weeks (IA-8 W) were separately assigned to two subgroups and fed either a control diet (CD, 10 kJ% from fat) or HFD (60 kJ% from fat) for 9 months followed by an analysis focused on metabolic, emotional behavioral, and neuroplastic profiles. RESULTS: The results illustrated that, in addition to abnormal glucolipid metabolism and insulin sensitivity, mice on a chronic HFD exhibited increased levels of anxiety and depression-like behaviors and aberrant hippocampal neuroplasticity. When compared with IA-8 W mice, several changes indicating systemic metabolic disturbance and neurobehavioral disorder after chronic HFD consumption were aggravated in IA-4 W mice, accompanied by exaggerated impairments in hippocampal insulin sensitivity and neurogenesis. CONCLUSIONS: These results not only provide in vivo evidence that the juvenile stage is a critical period of vulnerability to detrimental effects of HFD consumption on metabolic and neuronal function but also suggest dampened hippocampal insulin signaling as a potential link between prolonged HFD consumption and negative neurobehavioral outcomes. Considering the substantial burden posed by psychiatric disorders and the high prevalence of HFD among youth, these observations are meaningful for raising awareness of the harmful effects of excessive dietary fat intake and developing strategy for preventing mental disorders.

High-Fat Diet Consumption in Adolescence Induces Emotional Behavior Alterations and Hippocampal Neurogenesis Deficits Accompanied by Excessive Microglial Activation.

Adolescence is a developmental epoch characterized by massive neural circuit remodeling; thus, the brain is particularly vulnerable to environmental influences during this period. Excessive high-fat diet (HFD) consumption, which is very common among adolescents, has long been recognized as a potent risk factor for multiple mood disorders, including depression and anxiety. However, the precise mechanisms underlying the influences of HFD consumption in adolescence on emotional health are far from clear. In the present study, C57BL/6 mice were fed a control diet (CD) or HFD for about 4 weeks from postnatal day (P) 28 to P60, spanning most of the adolescence period, and then subjected to behavioral assessments and histological examinations. HFD mice exhibited elevated levels of depression and anxiety, decreased hippocampal neurogenesis, and excessive microglial activation in the ventral hippocampus. Furthermore, in HFD-fed mice, microglia showed increased DCX+ inclusions, suggesting aberrant microglial engulfment of newborn neurons in HFD-fed adolescents. To our knowledge, this is the first observation suggesting that the negative effects of HFD consumption in adolescence on emotion and neuroplasticity may be attributed at least in part to aberrant microglial engulfment of nascent neurons, extending our understanding of the mechanism underlying HFD-related affective disorders in young people.

Progranulin modulates cartilage-specific gene expression via sirtuin 1-mediated deacetylation of the transcription factors SOX9 and P65.

Progranulin (PGRN) is an autocrine growth factor that exerts crucial roles within cartilage tissue; however, the molecular mechanisms underlying PGRN-mediated cartilage homeostasis remain elusive. In the present study, we investigated the role of PGRN in regulating chondrocyte homeostasis and its therapeutic potential for managing osteoarthritis (OA). We found that PGRN levels are significantly increased in human cartilage in mild OA and that its expression is decreased in the cartilage in severe OA. In vitro, treatment of primary rat chondrocytes with recombinant PGRN significantly enhanced the levels of collagen type II α 1 chain (COL2A1) and aggrecan, and attenuated TNFα-induced up-regulation of matrix metallopeptidase 13 (MMP13) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) in chondrocytes. These effects were abrogated in SIRT1-/- cells, indicating a causative role of SIRT1 in the effects of PGRN on protein expression in chondrocytes. Mechanistically, PGRN increased SIRT1 expression and activity, which reduced the acetylation levels of SRY-box transcription factor (SOX9) and transcription factor P65 (P65) and thereby promoted nuclear translocation of SOX9 and inhibited TNFα-induced P65 nuclear accumulation to maintain chondrocyte homeostasis. In conclusion, our findings reveal a mechanism of action for PGRN that maintains cartilage homeostasis and supports the notion that PGRN up-regulation may be a promising strategy for managing OA.

Recyclable Luminescence Sensor for Dinotefuran in Water by Stable Cadmium-Organic Framework.

Due to the widespread use of dinotefuran around the world, its impact on food and environmental safety has aroused great concern, and the establishment of a rapid and convenient approach for dinotefuran detection is necessary but challenging. Herein, we synthesized a unique three-dimensional framework {[(CH3)2NH2]2[Cd3(BCP)2]·10H2O·3.5DMF}n (1). Single-crystal X-ray analysis indicates that 1 possesses a 4,8-connected anion framework that corresponds to alb topology, with a one-dimensional rectangular channel along the c-axis with the size of 4 Å × 10 Å. Compound 1 displays satisfactory solvent and thermal stability. Luminescent investigations reveal that 1 can selectively detect dinotefuran by fluorescence quenching among other pesticides, displaying excellent anti-interference performance with common ions in water. Importantly, the limit of detection is as low as 2.09 ppm, which is far below the residual concentration of the U.S. food standard. A fluorescence quenching mechanism study shows that there exists competitive energy absorption and static quenching processes. To our knowledge, 1 is the first MOF-based fluorescence probe for dinotefuran detection.

Decidua-derived granulocyte macrophage colony-stimulating factor induces polymorphonuclear myeloid-derived suppressor cells from circulating CD15+ neutrophils.

STUDY QUESTION: Do decidua-derived factors stimulate the conversion of circulating neutrophils to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in early human pregnancy? SUMMARY ANSWER: Circulating neutrophils can acquire PMN-MDSC-like phenotypes and function via phosphorylated signal transducer and activator of transcription 5/programmed death ligand 2 (pSTAT5/PD-L2) signalling after stimulation with decidua-derived granulocyte macrophage colony-stimulating factor (GM-CSF). WHAT IS KNOWN ALREADY: PMN-MDSCs are an important immunoregulatory cell type in early pregnancy. Neutrophils are of high heterogeneity and plasticity and can polarize to immunosuppressive PMN-MDSCs upon stimulation. STUDY DESIGN, SIZE, DURATION: For analysis of myeloid-derived suppressor cell (MDSC) subset proportions, 12 endometrium tissues and 12 peripheral blood samples were collected from non-pregnant women, and 40 decidua tissues and 16 peripheral blood samples were obtained from women with normal early pregnancy undergoing elective surgical pregnancy termination for nonmedical reasons with gestation age of 6-10 weeks. Twenty-nine decidua tissues were collected for isolation of CD15+ PMN-MDSCs. Twenty endometrium tissues and 30 decidua tissues were collected for cytokine analysis, immunohistochemistry or neutrophil stimulation. Peripheral blood samples were obtained from 36 healthy donors for isolation of CD3+ T cells and CD15+ neutrophils. PARTICIPANTS/MATERIALS, SETTING, METHODS: The proportion of MDSC subsets in the decidua and peripheral blood of normal early pregnancy, endometrium and peripheral blood of non-pregnant women was analysed by flow cytometry. The phenotypes and function of decidual PMN-MDSCs and circulating neutrophils were compared by flow cytometry. Circulating neutrophils were stimulated with decidual explant supernatant (DES) and the phenotypes were measured by flow cytometry and immunofluorescence. The suppressive capacity of decidual PMN-MDSCs and DES-conditioned neutrophils was analysed by flow cytometry with or without anti-programmed cell death-1 (PD-1) antibody. Cytokines from DES and endometrial explant supernatant (EES) were detected by a Luminex assay. GM-CSF expression was determined by ELISA and immunohistochemistry. Neutrophils were stimulated with DES, EES, DES with anti-GM-CSF antibody or EES with GM-CSF. CD11b, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), PD-L2 and pSTAT5 expression were measured by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of PMN-MDSCs was significantly increased in the decidua of early pregnancy compared with peripheral blood of non-pregnant women, the endometrium of non-pregnant women or peripheral blood during early pregnancy. Decidual PMN-MDSCs suppressed T-cell proliferation and cytokine production. Phenotypes of decidual PMN-MDSCs were similar to mature activated neutrophils. DES-induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. The PD-L2 expression in neutrophils was dependent on STAT5 phosphorylation. Both decidual PMN-MDSCs and DES-conditioned neutrophils suppressed T-cell proliferation via PD-1 signalling. GM-CSF was up-regulated in the decidua and induced CD11b, LOX-1 and PD-L2 expression on neutrophils. DES significantly induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation. Anti-GM-CSF antibody remarkably blocked such stimulation in neutrophils. EES did not induce CD11b, LOX-1, PD-L2 expression or STAT5 phosphorylation, while GM-CSF treatment sufficiently stimulated CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The study was based on in vitro experiments and we were not able to evaluate neutrophils differentiation to PMN-MDSCs in other sites before entering the maternal-foetal interface due to the limited availability of human samples. This needs to be explored using murine models. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study demonstrating that decidual PMN-MDSCs are a group of immunoregulatory cells with mature status, and that neutrophils can be induced to a PMN-MDSC-like phenotype with decidua-derived GM-CSF via pSTAT5/PD-L2 signalling. This study indicates that GM-CSF can facilitate immune tolerance of early pregnancy through regulating PMN-MDSCs and further provides a potential role of GM-CSF in prevention and treatment for pregnancy complications. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (81671481) and National Natural Science Foundation of China (81871179). All authors have no competing interests to declare.

Sirtuin-1 (SIRT1) stimulates growth-plate chondrogenesis by attenuating the PERK-eIF-2α-CHOP pathway in the unfolded protein response.

The NAD+-dependent deacetylase sirtuin-1 (SIRT1) has emerged as an important regulator of chondrogenesis and cartilage homeostasis, processes that are important for physiological skeletal growth and that are dysregulated in osteoarthritis. However, the functional role and underlying mechanism by which SIRT1 regulates chondrogenesis remain unclear. Using cultured rat metatarsal bones and chondrocytes isolated from rat metatarsal rudiments, here we studied the effects of the SIRT1 inhibitor EX527 or of SIRT1 siRNA on chondrocyte proliferation, hypertrophy, and apoptosis. We show that EX527 or SIRT1 siRNA inhibits chondrocyte proliferation and hypertrophy and induces apoptosis. We also observed that SIRT1 inhibition mainly induces the PERK-eIF-2α-CHOP axis of the endoplasmic reticulum (ER) stress response in growth-plate chondrocytes. Of note, EX527- or SIRT1 siRNA-mediated inhibition of metatarsal growth and growth-plate chondrogenesis were partly neutralized by phenylbutyric acid, a chemical chaperone that attenuates ER stress. Moreover, EX527-mediated impairment of chondrocyte function (i.e. of chondrocyte proliferation, hypertrophy, and apoptosis) was partly reversed in CHOP-/- cells. We also present evidence that SIRT1 physically interacts with and deacetylates PERK. Collectively, our findings indicate that SIRT1 deacetylates PERK and attenuates the PERK-eIF-2α-CHOP axis of the unfolded protein response pathway and thereby promotes growth-plate chondrogenesis and longitudinal bone growth.

Characteristics of midluteal phase uterine artery hemodynamics in patients with recurrent pregnancy loss.

AIM: To study the association in resistance to uterine artery blood flow and recurrent pregnancy loss (RPL) and find its potential influencing factors. METHODS: A retrospective study was conducted in 870 RPL and 237 non-RPL patients visiting to the Clinic from January 2014 to February 2018. All participants underwent comprehensive examinations and were scanned by transvaginal Doppler ultrasonography during the midluteal phase to measure the pulsatility index (PI), resistance index (RI) and systolic/diastolic ratio (S/D) values of the left and right main uterine arteries. P value less than 0.05 was considered statistically significant. RESULTS: The mean PI, RI and S/D values for uterine arteries were significantly higher in RPL patients than in non-RPL patients (P < 0.001). When subjects were grouped according to the different etiologies of RPL, significant higher indices of uterine arteries were found in RPL patients with antiphospholipid syndrome (P < 0.001), autoimmune diseases (P < 0.001), endocrinological abnormalities (P < 0.05), thrombophilia (P < 0.001), uterine anomalies (P < 0.01) and unexplained RPL (P < 0.001). No differences were found between patients with chromosomal anomalies and uterine arteries blood flow (P > 0.05). In RPL patients, mean PI, mean RI and mean S/D values shows no difference among groups (P > 0.05). The Similar results were observed in age and number of spontaneous abortion (P > 0.05). CONCLUSION: Impaired uterine artery blood perfusion may be an underlying pathology to RPL, and it can be used as an independent risk factor for pregnancy failure.

Prevalence of depression and anxiety in women with recurrent pregnancy loss and the associated risk factors.

OBJECTIVE: To investigate the prevalence and explore potential risk factors of depression and anxiety in patients with recurrent pregnancy loss (RPL). METHODS: 1138 non-pregnant women aged 20-40 years old who attempted to conceive were invited to complete a questionnaire, including basic information, Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS). RESULTS: 782 RPL women, 218 women with one pregnancy loss and 138 women with no history of pregnancy loss were included in this study. We found that both RPL patients and women with one pregnancy loss had significantly higher SDS and SAS scores than the control group (P = 0.006, 0.003). Furthermore, in RPL patients, those with lower education level (lower than university), lower household income (< 10,000 yuan) and history of induced abortion had significantly higher levels of depression and anxiety. Women with multiple pregnancy losses ( ≥ 3) and no live birth had significantly higher SDS scores. Women who had been married for 3 years or more had a significantly higher SAS score. Logistic regression revealed that lower education level (lower than university) was an independent risk factor for depression (adjusted OR = 1.75, 95% CI 1.10-2.77, P = 0.018) and anxiety (adjusted OR = 1.80, 95% CI 1.04-3.13, P = 0.037), and women with three or more pregnancy losses had increased odds of depression than those with two pregnancy losses (adjusted OR = 1.82, 95% CI 1.15-2.88, P = 0.012). CONCLUSION: RPL patients are more likely to develop depression and anxiety than women with no history of pregnancy loss. Lower education level and multiple pregnancy losses (≥ 3) appear to be two independent risk factors of depression and anxiety in women with RPL. Women with one pregnancy loss also show a significant higher level for depression and anxiety. Appropriate psychological intervention can be considered for such patients.

An Ultrastable Matryoshka [Hf13 ] Nanocluster as a Luminescent Sensor for Concentrated Alkali and Acid.

Stable metal clusters that can resist both highly concentrated acid and alkali are unknown. Herein, we present a discrete neutral cluster, Hf13 (µ4 -O)8 (OCH3 )36 (1), which features extraordinary chemical stability by preserving its crystalline state in concentrated aqueous solutions of both acid (10 m HNO3 ) and alkali (20 m boiling NaOH). Importantly, 1 can serve as a luminescent probe for detecting both concentrated alkali (20 m NaOH) and strong acid (1 m HNO3 ) with high selectivity and repeatability. DFT studies of the electronic structure and bonding revealed that 1 has an extremely large HOMO-LUMO gap due to strong d π-p π bonding that accounts for the ultrahigh stability.

A Novel Walking Detection and Step Counting Algorithm Using Unconstrained Smartphones.

Recently, with the development of artificial intelligence technologies and the popularity of mobile devices, walking detection and step counting have gained much attention since they play an important role in the fields of equipment positioning, saving energy, behavior recognition, etc. In this paper, a novel algorithm is proposed to simultaneously detect walking motion and count steps through unconstrained smartphones in the sense that the smartphone placement is not only arbitrary but also alterable. On account of the periodicity of the walking motion and sensitivity of gyroscopes, the proposed algorithm extracts the frequency domain features from three-dimensional (3D) angular velocities of a smartphone through FFT (fast Fourier transform) and identifies whether its holder is walking or not irrespective of its placement. Furthermore, the corresponding step frequency is recursively updated to evaluate the step count in real time. Extensive experiments are conducted by involving eight subjects and different walking scenarios in a realistic environment. It is shown that the proposed method achieves the precision of 93.76 % and recall of 93.65 % for walking detection, and its overall performance is significantly better than other well-known methods. Moreover, the accuracy of step counting by the proposed method is 95.74 % , and is better than both of the several well-known counterparts and commercial products.