MAMI: a comprehensive database of mother-infant microbiome and probiotic resources.

Extensive evidence has demonstrated that the human microbiome and probiotics confer great impacts on human health, particularly during critical developmental stages such as pregnancy and infancy when microbial communities undergo remarkable changes and maturation. However, a major challenge in understanding the microbial community structure and interactions between mothers and infants lies in the current lack of comprehensive microbiome databases specifically focused on maternal and infant health. To address this gap, we have developed an extensive database called MAMI (Microbiome Atlas of Mothers and Infants) that archives data on the maternal and neonatal microbiome, as well as abundant resources on edible probiotic strains. By leveraging this resource, we can gain profound insights into the dynamics of microbial communities, contributing to lifelong wellness for both mothers and infants through precise modulation of the developing microbiota. The functionalities incorporated into MAMI provide a unique perspective on the study of the mother-infant microbiome, which not only advance microbiome-based scientific research but also enhance clinical practice. MAMI is publicly available at https://bioinfo.biols.ac.cn/mami/.

Glutamine supplementation alleviated aortic atherosclerosis in mice model and in vitro.

This study aimed to clarify the role of glutamine in atherosclerosis and its participating mechanism. Forty C57BL/6J mice were divided into wild control (wild Con), ApoE- /- control (ApoE- /- Con), glutamine + ApoE- /- control (Glut + ApoE- /- Con), ApoE- /- high fat diet (ApoE- /- HFD), and glutamine + ApoE- /- HFD (Glut + ApoE- /- HFD) groups. The degree of atherosclerosis, western blotting, and multiomics were detected at 18 weeks. An in vitro study was also performed. Glutamine treatment significantly decreased the degree of aortic atherosclerosis (p = 0.03). O-GlcNAcylation (O-GlcNAc), IL-1ß, IL-1α, and pyruvate kinase M2 (PKM2) in the ApoE- /- HFD group were significantly higher than those in the ApoE- /- Con group (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05), and aggravated by O-GlcNA transferase (OGT) overexpression in the in vitro study (p < 0.05). Multiomics showed that the ApoE- /- HFD group had higher levels of oxidative stress regulatory molecules (guanine deaminase [GUAD], xanthine dehydrogenase [XDH]), proinflammatory regulatory molecules (myristic acid and myristoleic acid), and stress granules regulatory molecules (caprin-1 and deoxyribose-phosphate aldolase [DERA]) (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05). We conclude that glutamine supplementation might alleviate atherosclerosis through downregulation of O-GlcNAc, glycolysis, oxidative stress, and proinflammatory pathway.

Therapeutic intervention in neuroinflammation for neovascular ocular diseases through targeting the cGAS-STING-necroptosis pathway.

The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.

Enhancing Zn2+ Storage Performance by Constructing the Interfaces Between VO2 and Co-N-C Layers.

Vanadium oxides have aroused attention as cathode materials in aqueous zinc-ion batteries (AZIBs) due to their low cost and high safety. However, low ion diffusion and vanadium dissolution often lead to capacity decay and deteriorating stability during cycling. Herein, vanadium dioxides (VO2) nanobelts are coated with a single-atom cobalt dispersed N-doped carbon (Co-N-C) layer via a facile calcination strategy to form Co-N-C layer coated VO2 nanobelts (VO2@Co-N-C NBs) for cathodes in AZIBs. Various in-/ex situ characterizations demonstrate the interfaces between VO2 layers and Co-N-C layers can protect the VO2 NBs from collapsing, increase ion diffusion, and enhance the Zn2+ storage performance. Additional density functional theory (DFT) simulations demonstrate that Co─O─V bonds between VO2 and Co-N-C layers can enhance interfacial Zn2+ storage. Moreover, the VO2@Co-N-C NBs provided an ultrahigh capacity (418.7 mAh g-1 at 1 A g-1), outstanding long-term stability (over 8000 cycles at 20 A g-1), and superior rate performance.

LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity.

Histidine phosphorylation (pHis), occurring on the histidine of substrate proteins, is a hidden phosphoproteome that is poorly characterized in mammals. LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) is one of the histidine phosphatases and its encoding gene was recently identified as a susceptibility gene for major depressive disorder (MDD). However, little is known about how LHPP or pHis contributes to depression. Here, by using integrative approaches of genetics, behavior and electrophysiology, we observed that LHPP in the medial prefrontal cortex (mPFC) was essential in preventing stress-induced depression-like behaviors. While genetic deletion of LHPP per se failed to affect the mice's depression-like behaviors, it markedly augmented the behaviors upon chronic social defeat stress (CSDS). This augmentation could be recapitulated by the local deletion of LHPP in mPFC. By contrast, overexpressing LHPP in mPFC increased the mice's resilience against CSDS, suggesting a critical role of mPFC LHPP in stress-induced depression. We further found that LHPP deficiency increased the levels of histidine kinases (NME1/2) and global pHis in the cortex, and decreased glutamatergic transmission in mPFC upon CSDS. NME1/2 served as substrates of LHPP, with the Aspartic acid 17 (D17), Threonine 54 (T54), or D214 residue within LHPP being critical for its phosphatase activity. Finally, reintroducing LHPP, but not LHPP phosphatase-dead mutants, into the mPFC of LHPP-deficient mice reversed their behavioral and synaptic deficits upon CSDS. Together, these results demonstrate a critical role of LHPP in regulating stress-related depression and provide novel insight into the pathogenesis of MDD.

Targeted delivery of MerTK protein via cell membrane engineered nanoparticle enhances efferocytosis and attenuates atherosclerosis in diabetic ApoE-/- Mice.

BACKGROUND: Clearance of apoptotic cells by efferocytosis is crucial for prevention of atherosclerosis progress, and impaired efferocytosis contributes to the aggravated atherosclerosis. RESULTS: In this study, we found that diabetic ApoE-/- mice showed aggravated atherosclerosis as hyperglycemia damaged the efferocytosis capacity at least partially due to decreased expression of Mer tyrosine kinase (MerTK) on macrophages. To locally restore MerTK in the macrophages in the plaque, hybrid membrane nanovesicles (HMNVs) were thus developed. Briefly, cell membrane from MerTK overexpressing RAW264.7 cell and transferrin receptor (TfR) overexpressing HEK293T cell were mixed with DOPE polymers to produce nanovesicles designated as HMNVs. HMNVs could fuse with the recipient cell membrane and thus increased MerTK in diabetic macrophages, which in turn restored the efferocytosis capacity. Upon intravenous administration into diabetic ApoE-/- mice, superparamagnetic iron oxide nanoparticles (SMN) decorated HMNVs accumulated at the aorta site significantly under magnetic navigation, where the recipient macrophages cleared the apoptotic cells efficiently and thus decreased the inflammation. CONCLUSIONS:  Our study indicates that MerTK decrease in macrophages contributes to the aggravated atherosclerosis in diabetic ApoE-/- mice and regional restoration of MerTK in macrophages of the plaque via HMNVs could be a promising therapeutic approach.

Is cryoablation still suitable for advanced non-small cell lung cancer after failure of first-line chemotherapy? A multicenter, prospective, randomized-controlled trial of eighty-seven patients.

The aim of this study was to investigate the therapeutic effect of cryoablation treatment in advanced NSCLC patients who had failed first-line chemotherapy. Eighty-seven patients from ten hospitals in China were enrolled into the study, forty-four patients received cryoablation treatment plus basic treatment (experimental group), and forty-three patients had basic treatment alone (control group). Follow-up was performed once every three months until the end of the study or the death of the patient. The primary endpoints were overall and post-intervention survival; secondary endpoints included tumor markers, solid tumor efficacy, and symptom changes before and after treatment. There was no significant difference in median OS between the two groups of patients (9.0 months vs 11.2 months, P = 0.583). The disease control rate (DCR) and living quality of the experimental group was higher than that of the control group. In terms of OS, indiscriminate use of cryoablation for such patients was not beneficial, though it could improve symptoms of patients. Cryoablation had a significant effect on selected advanced NSCLC patients after the failure of first-line chemotherapy.

A specific RIP3+ subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism.

Retinal neovascularization is a leading cause of severe visual loss in humans, and molecular mechanisms of microglial activation-driven angiogenesis remain unknown. Using single-cell RNA sequencing, we identified a subpopulation of microglia named sMG2, which highly expressed necroptosis-related genes Rip3 and Mlkl. Genetic and pharmacological loss of function demonstrated that hypoxia-induced microglial activation committed to necroptosis through the RIP1/RIP3-mediated pathway. Specific deletion of Rip3 gene in microglia markedly decreased retinal neovascularization. Furthermore, hypoxia induced explosive release of abundant FGF2 in microglia through RIP3-mediated necroptosis. Importantly, blocking signaling components of the microglia necropotosis-FGF2 axis largely ablated retinal angiogenesis and combination therapy with simultaneously blocking VEGF produced synergistic antiangiogenic effects. Together, our data demonstrate that targeting the microglia necroptosis axis is an antiangiogenesis therapy for retinal neovascular diseases.

Perfluorooctane sulfonate induces ferroptosis-dependent non-alcoholic steatohepatitis via autophagy-MCU-caused mitochondrial calcium overload and MCU-ACSL4 interaction.

The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4，GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.

Simple Conditional Spatial Query Mask Deformable Detection Transformer: A Detection Approach for Multi-Style Strokes of Chinese Characters.

In the Chinese character writing task performed by robotic arms, the stroke category and position information should be extracted through object detection. Detection algorithms based on predefined anchor frames have difficulty resolving the differences among the many different styles of Chinese character strokes. Deformable detection transformer (deformable DETR) algorithms without predefined anchor frames result in some invalid sampling points with no contribution to the feature update of the current reference point due to the random sampling of sampling points in the deformable attention module. These processes cause a reduction in the speed of the vector learning stroke features in the detection head. In view of this problem, a new detection method for multi-style strokes of Chinese characters, called the simple conditional spatial query mask deformable DETR (SCSQ-MDD), is proposed in this paper. Firstly, a mask prediction layer is jointly determined using the shallow feature map of the Chinese character image and the query vector of the transformer encoder, which is used to filter the points with actual contributions and resample the points without contributions to address the randomness of the correlation calculation among the reference points. Secondly, by separating the content query and spatial query of the transformer decoder, the dependence of the prediction task on the content embedding is relaxed. Finally, the detection model without predefined anchor frames based on the SCSQ-MDD is constructed. Experiments are conducted using a multi-style Chinese character stroke dataset to evaluate the performance of the SCSQ-MDD. The mean average precision (mAP) value is improved by 3.8% and the mean average recall (mAR) value is improved by 1.1% compared with the deformable DETR in the testing stage, illustrating the effectiveness of the proposed method.

DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors.

Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1ß (NRXN1ß) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs.SIGNIFICANCE STATEMENTDSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1ß interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.

FOXF2 oppositely regulates stemness in luminal and basal-like breast cancer cells through the Wnt/beta-catenin pathway.

The stemness of cancer cells contributes to tumorigenesis, the heterogeneity of malignancies, cancer metastasis, and therapeutic resistance. However, the roles and regulatory mechanisms maintaining stemness among breast cancer subtypes remain elusive. Our previous studies have demonstrated that ectopic expression and dynamic alteration of the mesenchymal transcription factor forkhead box F2 (FOXF2) differentially regulates breast cancer progression and metastasis organotropism in a cell subtype-specific manner. Here, we reveal the underlying mechanism by which FOXF2 enhances stemness in luminal breast cancer cells but suppresses that in basal-like breast cancer (BLBC) cells. We show that luminal breast cancer and BLBC cells with FOXF2-regulated stemness exhibit partial mesenchymal stem cell properties that toward osteogenic differentiation and myogenic differentiation, respectively. Furthermore, we show that FOXF2 activates the Wnt signaling pathway in luminal breast cancer cells but represses this pathway in BLBC cells by recruiting nuclear receptor coactivator 3 (NCoA3) and nuclear receptor corepressor 1 (NCoR1) to the promoters of Wnt family member 2B (WNT2B) and frizzled class receptor 1 (FZD1) genes to activate and repress their transcription, respectively. We propose that targeting the Wnt signaling pathway is a promising strategy for the treatment of breast cancers with dysregulated expression of FOXF2.

Hyperuricemia as an independent risk factor for metabolic dysfunction-associated fatty liver disease in nonobese patients without type 2 diabetes mellitus.

According to the latest consensus statement, fatty liver complicated by specific metabolic abnormalities can be diagnosed as metabolic dysfunction-associated fatty liver disease (MAFLD) in nonobese patients without type 2 diabetes mellitus (T2DM). However, hyperuricemia (HUA), a manifestation of metabolic disorders, is excluded from diagnostic criteria. This study explored the association between HUA and MAFLD in nonobese patients without T2DM. A total of 28,187 participants were recruited from the Examination Center of the China-Japan Friendship Hospital from 2018 to 2022 and divided into four subgroups: nonobese patients without T2DM, obese patients without T2DM, nonobese patients with T2DM, and obese patients with T2DM. MAFLD was diagnosed by ultrasound combined with laboratory examinations. The association of HUA with MAFLD subgroups was performed by logistical regression analysis. The predictive ability of UA for MAFLD subgroups was assessed by receiver operating characteristics (ROC). HUA was positively associated with MAFLD in nonobese patients without T2DM in both males and females, even after adjusting for sex, BMI, dyslipidemia, and abnormal liver function. The association increased gradually with aging, especially in those over 40 yr old. HUA was an independent risk factor for MAFLD in nonobese patients without T2DM. We suggest that UA abnormalities might be considered in the diagnosis of MAFLD in nonobese patients without T2DM.NEW & NOTEWORTHY HUA is an independent risk factor for MAFLD in nonobese patients without T2DM. The association of HUA with MAFLD in nonobese patients without T2DM increased gradually with aging, especially in those over 40 yr old. In nonobese patients without T2DM, univariate analysis showed that females with HUA had a higher risk of MAFLD than males. However, the difference was narrowed after adjustment for confounders.

Increasing LRP4 diminishes neuromuscular deficits in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive wasting of skeletal muscles. The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, critical for the control of muscle contraction. The NMJ decline is observed in DMD patients, but the mechanism is unclear. LRP4 serves as a receptor for agrin, a proteoglycan secreted by motor neurons to induce NMJ, and plays a critical role in NMJ formation and maintenance. Interestingly, we found that protein levels of LRP4 were reduced both in muscles of the DMD patients and DMD model mdx mice. We explored whether increasing LRP4 is beneficial for DMD and crossed muscle-specific LRP4 transgenic mice with mdx mice (mdx; HSA-LRP4). The LRP4 transgene increased muscle strength, together with improved neuromuscular transmission in mdx mice. Furthermore, we found the LRP4 expression mitigated NMJ fragments and denervation in mdx mice. Mechanically, we showed that overexpression of LRP4 increased the activity of MuSK and expression of dystrophin-associated glycoprotein complex proteins in the mdx mice. Overall, our findings suggest that increasing LRP4 improves both function and structure of NMJ in the mdx mice and Agrin signaling might serve as a new therapeutic strategy in DMD.

Identification of fluorescent aerosol observed by a spectroscopic lidar over northwest China.

Bioaerosols play a significant role in climate change and variation of ecological environment. To investigate characterization of atmospheric bioaerosols, we conducted lidar measurement for observing bioaerosols close to dust sources over northwest China in April, 2014. The developed lidar system can not only allowed us to measure the 32-channel fluorescent spectrum between 343 nm to 526 nm with a spectral resolution of 5.8 nm but also simultaneously detect polarisation measurements at 355 nm and 532 nm, as well as Raman scattering signals at 387 nm and 407 nm. According to the findings, the lidar system was able to pick up the robust fluorescence signal emitted by dust aerosols. Especially the polluted dust, the fluorescence efficiency could reach 0.17. In addition, the efficiency of single-band fluorescence typically rises as the wavelength goes up and the ratio of fluorescence efficiency of polluted dust, dust, air pollutant and background aerosols is about 4:3:8:2. Moreover, our results demonstrate that simultaneous measurements of depolarization at 532 nm and fluorescence could better distinguish fluorescent aerosols than those at 355 nm. This study enhances the ability of laser remote sensing for real-time detecting bioaerosol in the atmosphere.

Method for retrieving range-resolved aerosol microphysical properties from polarization lidar measurements.

Aerosol microphysical properties, such as volume concentration (VC) and effective radius (ER), are of great importance to evaluate their radiative forcing and impacts on climate change. However, range-resolved aerosol VC and ER still cannot be obtained by remote sensing currently except for the column-integrated one from sun-photometer observation. In this study, a retrieval method of range-resolved aerosol VC and ER is firstly proposed based on the partial least squares regression (PLSR) and deep neural networks (DNN), combining polarization lidar and collocated AERONET (AErosol RObotic NETwork) sun-photometer observations. The results show that the measurement of widely-used polarization lidar can be reasonably used to derive the aerosol VC and ER, with the determination coefficient (R2) of 0.89 (0.77) for VC (ER) by use of the DNN method. Moreover, it is proven that the lidar-based height-resolved VC and ER at near-surface are well consistent with independent observations of collocated Aerodynamic Particle Sizer (APS). Additionally, we found that there are significant diurnal and seasonal variations of aerosol VC and ER in the atmosphere at Semi-Arid Climate and Environment Observatory of Lanzhou University (SACOL). Compared with columnar ones from the sun-photometer observation, this study provides a reliable and practical way to obtain full-day range-resolved aerosol VC and ER from widely-used polarization lidar observation, even under cloud conditions. Moreover, this study also can be applied to long-term observations by current ground-based lidar networks and spaceborne CALIPSO lidar, aiming to further evaluate aerosol climatic effects more accurately.

Simulated depolarization ratios for dust and smoke at laser wavelengths: implications for lidar application.

Polarization measurements have been widely used to detect aerosol properties by remote sensing in recent decades. To better understand the polarization characteristics of aerosols by lidar, the numerically exact T-matrix method was used to simulate the depolarization ratio (DR) of dust and smoke aerosols at typical laser wavelengths in this study. The results show that the DRs of dust and smoke aerosols have obviously different spectral dependences. Moreover, the ratio of DRs at two wavelengths has an obvious linear relationship with the microphysical properties of aerosols, including aspect ratio, effective radius and complex refractive index. At short wavelengths, we can use it to invert the absorption characteristics of particles, further improving the detection ability of lidar. Comparing the simulation results of different channels, DR, (color ratio) CR and (lidar ratio) LR have a good logarithmic fitting relationship at 532 nm and 1064 nm, which helps to classify the aerosol types. On this basis, a new inversion algorithm, "1ß+1α+2δ", was presented. By this algorithm, the backscattering coefficient (ß), extinction coefficient (α), DR (δ) at 532 nm and 1064 nm can be used to expand the range of inversion and compare lidar data with different configurations to obtain more extensive optical characteristics of aerosols. Our study enhances the application of laser remote sensing in aerosol observations more accurately.

Hypoxia Inhibitor Combined with Chemotherapeutic Agents for Antitumor and Antimetastatic Efficacy against Osteosarcoma.

Chemotherapy is the main treatment method for osteosarcoma in the clinic. However, drug resistance and its poor antimetastatic effects greatly limit its clinical application. In this work, dual-drug nanoparticles (NPs) containing albendazole (ABZ) and doxorubicin (DOX), named AD@PLGA-PEG NPs, were prepared to solve the problems of chemotherapeutic drug resistance and poor antimetastasis effects. Compared with free DOX, ABZ combined with DOX can increase intracellular reactive oxygen species (ROS) and induce more tumor cell apoptosis; therefore, AD@PLGA-PEG NPs produced more mitochondria-mediated oxidative stress and better apoptosis efficiency. Importantly, ABZ can also effectively inhibit the expression of hypoxia inducible factor-1α (HIF-1α) and then reduce the expression of its downstream vascular endothelial growth factor (VEGF); thus, the AD@PLGA-PEG NPs effectively inhibited tumor metastasis in vivo. Collectively, the dual-drug AD@PLGA-PEG NPs delivery system provided prominent antitumor and antimetastatic efficacy and might be a promising treatment for osteosarcoma.

Cocrystal Synthesis through Crystal Structure Prediction.

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all the possible crystalline solid forms of small-molecule active pharmaceutical ingredients. We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. For MK-8876, the CSP-based cocrystal prediction was performed retrospectively and successfully predicted the maleic acid cocrystal as the most likely cocrystal to be observed. The triol is known to form two different cocrystals with 1,4-diazabicyclo[2.2.2]octane (DABCO), but a larger solid form landscape was desired. CSP-based cocrystal screening predicted the triol-DABCO cocrystal as rank one, while a triol-l-proline cocrystal was predicted as rank two. Computational finite-temperature corrections enabled determination of relative crystallization propensities of the triol-DABCO cocrystals with different stoichiometries and prediction of the triol-l-proline polymorphs in the free-energy landscape. The triol-l-proline cocrystal was obtained during subsequent targeted cocrystallization experiments and was found to exhibit an improved melting point and deliquescence behavior over the triol-free acid, which could be considered as an alternative solid form in the synthesis of islatravir.

Exosomes derived from mesenchymal stromal cells promote bone regeneration by delivering miR-182-5p-inhibitor.

Exosomes, small extracellular vesicles that function as a key regulator of cell-to-cell communication, are emerging as a promising candidate for bone regeneration. Here, we aimed to investigate the effect of exosomes from pre-differentiated human alveolar bone-derived bone marrow mesenchymal stromal cells (AB-BMSCs) carrying specific microRNAs on bone regeneration. Exosomes secreted from AB-BMSCs pre-differentiated for 0 and 7 days were cocultured with BMSCs in vitro to investigate their effect on the differentiation of the BMSCs. MiRNAs from AB-BMSCs at different stages of osteogenic differentiation were analyzed. BMSCs seeded on poly-L-lactic acid(PLLA) scaffolds were treated with miRNA antagonist-decorated exosomes to verify their effect on new bone regeneration. Exosomes pre-differentiated for 7 days effectively promoted the differentiation of BMSCs. Bioinformatic analysis revealed that miRNAs within the exosomes were differentially expressed, including the upregulation of osteogenic miRNAs (miR-3182, miR-1468) and downregulation of anti-osteogenic miRNAs (miR-182-5p, miR-335-3p, miR-382-5p), causing activation of the PI3K/Akt signaling pathway. The treatment of BMSC-seeded scaffolds with anti-miR-182-5p decorated exosomes demonstrated enhanced osteogenic differentiation and efficient formation of new bone. In conclusion, Osteogenic exosomes secreted from pre-differentiated AB-BMSCs were identified and the gene modification of exosomes provides great potential as a bone regeneration strategy. DATA AVAILABILITY STATEMENT: Data generated or analyzed in this paper partly are available in the GEO public data repository(http://www.ncbi.nlm.nih.gov/geo).