Westerly-triggered lake-effect snowfall enhanced with climate warming over the Tibetan Plateau.

Lake-effect snowfall (LES) occurs when cold air moves across open lakes. LES is expected to occur more frequently over the TP, due to the intensified lake expansion caused by intensified global warming. Thus, there is an urgent need to comprehensively assess the LES over the TP. Here, we revealed that the LES is triggered by westerly southward shift leading to the drop in air temperature and is positively correlated with lake area, wind speed and longitude across 12 large lakes (>300 km2) based on satellite observations and reanalysis data. Using a sensitivity model simulation, we determined that large lakes in the southern TP contributed to more than 50% of the snowfall in the downwind area in 2013. Projections indicate that the westerly-triggered LES will increase under the future RCP4.5 climate warming scenario, highlighting the importance of developing adaptive policies to address the growing risks associated with future LES.

Enhanced glacial lake activity threatens numerous communities and infrastructure in the Third Pole.

Glacial lake outburst floods (GLOFs) are among the most severe cryospheric hazards in the Third Pole, encompassing the Tibetan Plateau and surrounding Himalayas, Hindu Kush, and Tianshan Mountains. Recent studies on glacial lake changes and GLOF characteristics and risks in this region have shown scattered and insufficiently detailed features. Here, we conduct an appraisal of the GLOF risks by combining high-resolution satellite images, case-by-case high-precision GLOF modeling, and detailed downstream exposure data. The glacial lake changes from 2018 to 2022 in the region were primarily driven by the accelerated expansion of proglacial lakes. The GLOF frequency has exhibited a significant increasing trend since 1980, with intensified activity in Southeastern Tibet and the China-Nepal border area over the past decade. Approximately 6,353 km2 of land could be at risk from potential GLOFs, posing threats to 55,808 buildings, 105 hydropower projects, 194 km2 of farmland, 5,005 km of roads, and 4,038 bridges. This study directly responds to the need for local disaster prevention and mitigation strategies, highlighting the urgent requirement of reducing GLOF threats in the Third Pole and the importance of regional cooperation.

Total mesialization of the mandibular dentition using a mini-implant-supported device : A finite element analysis.

PURPOSE: Total mandibular arch mesialization using mini-implants is challenging due to anatomic limitations. The aim of this study was to introduce a mini-implant-supported device for total mesialization of the mandibular dentition and to analyze the biomechanical properties of the device. METHODS: Finite element models were constructed to explore the effect of friction and force direction on the force transmission efficiency of the device. In addition, the three-dimensional displacement of each tooth was evaluated with two force application points (2 or 8 mm hooks) under three force conditions (symmetric: 150 g of force on both sides, or asymmetric: 100 and 200 g of force on each side). RESULTS: The force transmission efficiency was 66.7% under a friction coefficient of 0.15 and parallel pushing and pulling forces. The force transmission efficiency was 65.90 and 66.63% when the pushing force was 15° away from the pulling force on the sagittal and horizontal planes, respectively. The mandibular dentition moved mesially with a greater tendency for incisor labial crown tipping, mesial molar rotation and buccal second molar crown tipping when using the 8 mm hook compared to that when using the 2 mm hook. Rigid archwires resulted in more consistent tooth mesialization than stainless steel archwires. Asymmetric forces resulted in asymmetric dental arch mesialization. CONCLUSION: The forces transmitted by the presented mini-implant-supported device varied depending on the friction level and force direction. The device should be able to achieve symmetric or asymmetric total mesialization of the mandibular dentition.

Aging-related decrease of histone methyltransferase SUV39H1 in adipose-derived stem cells enhanced SASP.

Aging-related diseases are closely associated with the state of inflammation, which is known as "inflammaging." Senescent cells are metabolically active, as exemplified by the secretion of inflammatory cytokines, chemokines, and growth factors, which is termed the senescence-associated secretory phenotype (SASP). Epigenetic regulation, especially the structural regulation of chromatin, is closely linked to the regulation of SASP. In our previous study, the suppressor of variegation 3-9 homolog 1 (SUV39H1) was elucidated to interact with Lhx8 and determine the cell fate of mesenchyme stem cells. However, the function of SUV39H1 during aging and the underlying mechanism of its epigenetic regulation remains controversial. Therefore, the C57BL/6 J CAG-Cre; SUV39H1fl/fl knockout mice and irradiation-induced cellular senescence model were built in this study to deepen the understanding of epigenetic regulation by SUV39H1 and its relation to SASP. In vivo and in vitro studies demonstrated that SUV39H1 decreased with aging and served as an inhibitor of SASP, especially IL-6, MCP-1, and Vcam-1, by altering H3K9me3 enrichment in their promoter region. These results provide new insights into the epigenetic regulation of SASP.

"Domino" cascade reactor based on DNA hydrogel for synergistic treatment of malignant tumor.

The action pathways of starvation therapy and photodynamic therapy (PDT) do not exist in isolation and are usually related to tumor cell metabolism and immune regulation, which are of great significance in the treatment of malignant tumors. Here, a cancer-targeted "domino" cascade reactor is constructed for synergistic starvation therapy and amplifies photodynamic therapy by assembling hemin and glucose oxidase (GOx) into DNA hydrogel load with hypoxia-inducible factor 1α (HIF-1α) and photosensitizer chlorin e6 (Ce6). The cascade reactor has excellent biocompatibility and tumor targeting, which promotes PDT by reducing HIF-1α. At the same time, the G-quadruplex of AS1411 combined with hemin (AH) catalyzes the generation of oxygen from hydrogen peroxide to further improve the efficiency of PDT. The synergistic therapeutic effect of the cascade reactor is evaluated through in vivo and in vitro experiments, indicating that this cascade reactor has great potential advantages in the synergistic treatment of cancer.

Genetically engineered CXCR4-modified exosomes for delivery of miR-126 mimics to macrophages alleviate periodontitis.

Biofilm-related diseases are a group of diseases that tolerate antimicrobial chemotherapies and therefore are refractory to treatment. Periodontitis, a non-device chronic biofilm disease induced by dental plaque, can serve as an excellent in vivo model to study the important effects of host factors on the biofilm microenvironment. Macrophage activity is one of the key factors that modulate the progression of inflammation-driven destruction in periodontitis; therefore it is an important host immunomodulatory factor. In this study, the reduction of microRNA-126 (miR-126) with the recruitment of macrophages in periodontitis was confirmed in clinical samples, and a strategy for targeted delivery of miR-126 to macrophages was explored. Exosomes overexpressing the C-X-C motif chemokine receptor 4 (CXCR4) loaded with miR-126 (CXCR4-miR126-Exo) was successfully constructed, which reduced off-target delivery to macrophages and regulated macrophages toward the anti-inflammatory phenotype. In vivo local injection of CXCR4-miR126-Exo into sites of periodontitis in rats effectively reduced bone resorption and osteoclastogenesis and inhibited the progression of periodontitis. These results provide new insights for designing novel immunomodulatory factor targeted delivery systems to treat periodontitis and other biofilm-related diseases.

Drug-Induced Self-Assembly Cascade Nanoreactor for Synergistic Tumor Therapy.

The construction of completely biocompatible and biodegradable tumor suppressors by a simple and reliable method is essential for the clinical application of cancer-targeted drugs. Herein, by inserting glucose oxidase (GOx), catalase (CAT), and chlorin e6 (Ce6) into human serum albumin (HSA) assembly molecules, we constructed a cancer-targeted cascade bioreactor for synergistic starvation and photodynamic therapy (PDT). The modification of HSA could block the GOx activity and reduce the cytotoxicity of normal cells and organs. Through active targeting and passive enhanced permeability and retention effect, the loading of AS1411 could promote the cascade bioreactors to effectively target nucleolin-overexpressed tumors. Once internalized by cancer cells, as a result of catalyzing hydrogen peroxide (H2O2) to produce oxygen (O2), the protein nano-cascade reactor promoted microenvironmental oxygenation, which would subsequently lead to an increase in cytotoxic singlet oxygen (1O2) production under light irradiation as well as the decomposition of intracellular glucose. In vitro and in vivo studies showed that the cascaded nanoreactors could significantly enhance therapeutic efficacy through synergistic starvation therapy and enhanced PDT as well as chemotherapy. This cascade strategy will be demonstrated in clinical applications with huge potential.

Synergistic osteogenic and angiogenic effects of KP and QK peptides incorporated with an injectable and self-healing hydrogel for efficient bone regeneration.

Irregular defects generated by trauma or surgery in orthopaedics practice were usually difficult to be fitted by the preformed traditional bone graft substitute. Therefore, the injectable hydrogels have attracted an increasing interest for bone repair because of their fittability and mini-invasivity. However, the uncontrollable spreading or mechanical failures during its manipulation remain a problem to be solved. Moreover, in order to achieve vascularized bone regeneration, alternatives of osteogenic and angiogenic growth factors should be adopted to avoid the problem of immunogenicity and high cost. In this study, a novel injectable self-healing hydrogel system (GMO hydrogel) loaded with KP and QK peptides had been developed for enhancing vascularized regeneration of small irregular bone defect. The dynamic imine bonds between gelatin methacryloyl and oxidized dextran provided the GMO hydrogel with self-healing and shear-thinning abilities, which led to an excellent injectability and fittability. By photopolymerization of the enclosed GelMA, GMO hydrogel was further strengthened and thus more suitable for bone regeneration. Besides, the osteogenic peptide KP and angiogenic peptide QK were tethered to GMO hydrogel by Schiff base reaction, leading to desired releasing profiles. In vitro, this composite hydrogel could significantly improve the osteogenic differentiation of BMSCs and angiogenesis ability of HUVECs. In vivo, KP and QK in the GMO hydrogel demonstrated a significant synergistic effect in promoting new bone formation in rat calvaria. Overall, the KP and QK loaded GMO hydrogel was injectable and self-healing, which can be served as an efficient approach for vascularized bone regeneration via a minimally invasive approach.

An integrative method for identifying potentially dangerous glacial lakes in the Himalayas.

Glacial lakes in the Himalayas are widely distributed. Since 1900, more than 100 glacial lake outburst floods (GLOFs) have originated in the region, causing approximately 7000 deaths and considerable economic losses. Identifying potentially dangerous glacial lakes (PDGLs) is considered the first step in assessing GLOF risks. In this study, a more thorough inventory of PDGLs was presented that included numerous small-sized glacial lakes (<0.1 km2) that were generally neglected in the Himalayas for decades. Moreover, the PDGL evaluation system was improved in response to several deficiencies, such as the selection of assessment factors, which are sometimes arbitrary without a solid scientific basis. We designed an optimality experiment to select the best combination of assessment factors from 57 factors to identify PDGLs. Based on the experiments on both drained and non-drained glacial lakes in the Sunkoshi Basin, eastern Himalayas, five assessment factors were determined to be the best combination: the mean slope of the parent glacier, the potential for mass movement into the lake, the mean slope of moraine dams, the watershed area, and the lake perimeter, corresponding to the GLOF triggers for ice avalanches, rockfalls and landslides, dam instability, heavy precipitation or other liquid inflows, and lake characteristics, respectively. We then applied the best combination of assessment factors to the 1650 glacial lakes with an area greater than 0.02 km2 in the Himalayas. We identified 207 glacial lakes as very high-hazard and 345 as high-hazard. It is noteworthy that in various GLOF susceptibility evaluation scenarios with different assessment factors, weighting schemes, and classification approaches, similar results for glacial lakes with high outburst potential have been obtained. The results provided here can be used as benchmark data to assess the GLOF risks for local communities.

Process, mechanisms, and early warning of glacier collapse-induced river blocking disasters in the Yarlung Tsangpo Grand Canyon, southeastern Tibetan Plateau.

Glacier collapse is a fairly new type of glacier-related disasters on the Asian Water Towers (AWTs) in the warming climate. On 16 October and 29 October 2018, two glacier collapses occurred in the Sedongpu Basin, 7 km downstream from Gyala Village, Paizhen Town, Miling County, on the Yarlung Tsangpo River (YTR). The ice and entrained debris flows caused by the glacier collapses blocked the YTR, resulting in a potential threat to residents and transport lines upstream and downstream. Through post-event field investigations with a helicopter and an unmanned aerial vehicle (UAV), remote sensing interpretation, and seismic, hydrological, and meteorological observations, the process and potential mechanisms of the glacier collapse-induced river blocking (GCRB) disasters were investigated. We confirmed that the first glacier collapse event occurred at 22:48 (Beijing time) on 16 October 2018 and the second began at 08:03 on 29 October 2018. Approximately 130 × 106 m3 of ice and debris detached from the glacier during the glacier collapse, and we calculated that the river blocking fans caused by the first and second glacier collapse event covered ~1.36 km2 and ~ 1.29 km2 on the main watercourse of the YTR, respectively. We determined that the GCRB incidents represent a disaster chain of glacier collapse → glacial debris flow → river blockage → dammed lake → outburst flood. These incidents arise due to a combination of factors, including glacier activity, climate warming, heavy precipitation, pre-seismic activity, and high topographic relief. In the context of climate warming on the Tibetan Plateau, such glacier collapse induced disaster chains will continue or even intensify in the future. To protect against glacier collapse disasters in the Grand Canyon on the YTR, we established a monitoring and early warning system (EWS), which has already successfully sounded alerts for GCRB incidents. As a major element of an integrated risk management strategy, the EWS represents a viable and promising tool for mitigating climate change-related risks.

Temporal induction of Lhx8 by optogenetic control system for efficient bone regeneration.

BACKGROUND: The spatiotemporal regulation of essential genes is crucial for controlling the growth and differentiation of cells in a precise manner during regeneration. Recently, optogenetics was considered as a potent technology for sophisticated regulation of target genes, which might be a promising tool for regenerative medicine. In this study, we used an optogenetic control system to precisely regulate the expression of Lhx8 to promote efficient bone regeneration. METHODS: Quantitative real-time PCR and western blotting were used to detect the expression of Lhx8 and osteogenic marker genes. Alkaline phosphatase staining and alizarin red staining were used to detect alkaline phosphatase activity and calcium nodules. A customized optogenetic expression system was constructed to regulate Lhx8, of which the expression was activated in blue light but not in dark. We also used a critical calvarial defect model for the analysis of bone regeneration in vivo. Moreover, micro-computed tomography (micro-CT), three-dimensional reconstruction, quantitative bone measurement, and histological and immunohistochemistry analysis were performed to investigate the formation of new bone in vivo. RESULTS: During the osteogenic differentiation of BMSCs, the expression levels of Lhx8 increased initially but then decreased thereafter. Lhx8 promoted the early proliferation of BMSCs but inhibited subsequent osteogenic differentiation. The optogenetic activation of Lhx8 in BMSCs in the early stages of differentiation by blue light stimulation led to a significant increase in cell proliferation, thus allowing a sufficient number of differentiating BMSCs to enter the later osteogenic differentiation stage. Analysis of the critical calvarial defect model revealed that the pulsed optogenetic activation of Lhx8 in transplanted BMSCs over a 5-day period led to a significant increase in the generation of bone in vivo. CONCLUSIONS: Lhx8 plays a critical role in balancing proliferation and osteogenic differentiation in BMSCs. The optogenetic activation of Lhx8 expression at early stage of BMSCs differentiation led to better osteogenesis, which would be a promising strategy for precise bone regeneration.

UV-curable hyperbranched polyester sealant with tunable mechanical properties.

Different types of wounds have different requirements of a wound sealant. One of the requirements of concern is the adaptability of the mechanical properties of biomaterials to native tissues. However, the mechanical properties of current sealant are untunable or adjustable in a small range normally. Therefore, the scope of application of these sealant is limited. In this study, we developed hyperbranched polyester (HBP)-based UV-curable sealant with tunable mechanical properties. This sealant was cured under UV-light for 2 minutes and exhibited strong adhesion with tissues. The shear adhesive strength of it to the porcine skin ranged between 20-30 kPa, which was higher than the fibrin glue (∼10 kPa). Moreover, the elastic modulus of the sealant in a tensile test ranged between 27-54 MPa, depending on the degree of acrylation of the HBPs. Additionally, we assessed the biocompatibility of the sealant by co-culturing it with mouse mesenchymal stem cells (mMSCs) for 7 days and discovered that the cell viability was unaffected. This sealant with a tunable elastic modulus might be a promising candidate for treating wounds with different elastic moduli.

FGF8 and BMP2 mediated dynamic regulation of dental mesenchyme proliferation and differentiation via Lhx8/Suv39h1 complex.

The homeobox gene, LIM-homeobox 8 (Lhx8), has previously been identified as an essential transcription factor for dental mesenchymal development. However, how Lhx8 itself is regulated and regulates odontogenesis remains poorly understood. In this study, we employed an RNAscope assay to detect the co-expression pattern of Lhx8 and Suv39h1 in the dental mesenchyme, which coincided with the dynamic expression profiles of the early epithelium signal of Fibroblast Growth Factor 8 (FGF8) and the later mesenchymal signal Bone Morphogenetic Protein 2 (BMP2). Moreover, FGF8 activated Lhx8, whereas BMP2 repressed Lhx8 expression at the transcriptional level. The high expression of Lhx8 in the early dental mesenchyme maintained the cell fate in an undifferentiated status by interacting with Suv39h1, a histone-lysine N-methyltransferase constitutively expressed in the dental mesenchyme. Further in the ex vivo organ culture model, the knockdown of Suv39h1 significantly blocked the function of Lhx8 and FGF8. Mechanistically, Lhx8/Suv39h1 recognized the odontoblast differentiation-related genes and repressed gene expression via methylating H3K9 on their promoters. Taken together, our data here suggest that Lhx8/Suv39h1 complex is inversely regulated by epithelium-mesenchymal signals, balancing the differentiation and proliferation of dental mesenchyme via H3K9 methylation.

RNA Hydrogel Combined with MnO2 Nanoparticles as a Nano-Vaccine to Treat Triple Negative Breast Cancer.

Hypoxia is not only the reason of tumor metastasis but also enhances the spread of cancer cells from the original tumor site, which results in cancer recurrence. Herein, we developed a self-assembled RNA hydrogel that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as MnO2 loaded-photodynamic agent chlorine e6 (MnO2@Ce6), and a chemotherapy drug doxorubicin (DOX) into MDA-MB-231cells. The RNA hydrogel consists of one tumour suppressor miRNA (miRNA-205) and one anti-metastatic miRNA (miRNA-182), both of which showed an outstanding effect in synergistically abrogating tumours. The hydrogel would be dissociated by endogenous Dicer enzyme to release loaded therapeutic molecules, and in the meantime induce decomposition of tumor endogenous H2O2 to relieve tumor hypoxia. As a result, a remarkable synergistic therapeutic effect is achieved through the combined chemo-photodynamic therapy, which simultaneously triggers a series of anti-tumor immune responses. Besides, the hydrogel as the carrier which modified aptamer to targeted MDA-MB-231 has the advantages of good biocompatibility and low cytotoxicity. This strategy could be implemented to design any other microRNA (miRNA) as the carrier, combined with other treatment methods to treat human cancer, thereby overcoming the limitations of current cancer therapies.

Biomineralization: An Opportunity and Challenge of Nanoparticle Drug Delivery Systems for Cancer Therapy.

Biomineralization is a common process in organisms to produce hard biomaterials by combining inorganic ions with biomacromolecules. Multifunctional nanoplatforms are developed based on the mechanism of biomineralization in many biomedical applications. In the past few years, biomineralization-based nanoparticle drug delivery systems for the cancer treatment have gained a lot of research attention due to the advantages including simple preparation, good biocompatibility, degradability, easy modification, versatility, and targeting. In this review, the research trends of biomineralization-based nanoparticle drug delivery systems and their applications in cancer therapy are summarized. This work aims to promote future researches on cancer therapy based on biomineralization. Rational design of nanoparticle drug delivery systems can overcome the bottleneck in the clinical transformation of nanomaterials. At the same time, biomineralization has also provided new research ideas for cancer treatment, i.e., targeted therapy, which has significantly better performance.

Control of mesenchymal stem cell biology by histone modifications.

Mesenchymal stem cells (MSCs) are considered the most promising seed cells for regenerative medicine because of their considerable therapeutic properties and accessibility. Fine-tuning of cell biological processes, including differentiation and senescence, is essential for achievement of the expected regenerative efficacy. Researchers have recently made great advances in understanding the spatiotemporal gene expression dynamics that occur during osteogenic, adipogenic and chondrogenic differentiation of MSCs and the intrinsic and environmental factors that affect these processes. In this context, histone modifications have been intensively studied in recent years and have already been indicated to play significant and universal roles in MSC fate determination and differentiation. In this review, we summarize recent discoveries regarding the effects of histone modifications on MSC biology. Moreover, we also provide our insights and perspectives for future applications.

Tooth Regeneration: Insights from Tooth Development and Spatial-Temporal Control of Bioactive Drug Release.

Tooth defect and tooth loss are common clinical diseases in stomatology. Compared with the traditional oral restoration treatment, tooth regeneration has unique advantages and is currently the focus of oral biomedical research. It is known that dozens of cytokines/growth factors and other bioactive factors are expressed in a spatial-temporal pattern during tooth development. On the other hand, the technology for spatial-temporal control of drug release has been intensively studied and well developed recently, making control release of these bioactive factors mimicking spatial-temporal pattern more feasible than ever for the purpose of tooth regeneration. This article reviews the research progress on the tooth development and discusses the future of tooth regeneration in the context of spatial-temporal release of developmental factors.

Contribution of the mandible position to the facial profile perception of a female facial profile: An eye-tracking study.

INTRODUCTION: Studies concerning the visual attention of laypersons viewing the soft tissue facial profile of men and women with malocclusion are lacking. This study aimed to determine the visual attention to the facial profile of patients with different levels of mandibular protrusion and facial background attractiveness using an eye-tracking device. METHODS: The scanning paths of 54 Chinese laypersons (50% female, 50% male, aged 18-23 years) were recorded by an eye-tracking device when they observed composite female facial profile images (n = 24), which were combinations of different degrees of mandibular protrusion (normal, slight, moderate, and severe) and different levels of facial background attractiveness (attractive, average, and unattractive). Dependent variables (fixation duration and first fixation time) were analyzed using repeated-measures factorial analysis of variance. RESULTS: For normal mandibular profiles, the fixation duration of the eyes was significantly higher than that of other facial features (P <0.001). The lower face and nose received the least attention. As the degree of protrusion increased from slight to moderate, more attention was drawn to the lower face accompanied by less attention to eyes in the unattractive group (P <0.05). When protrusion degree increased from moderate to severe, attention shifted from nose to lower face significantly in the attractive group (P <0.05). Attention shift from eyes to lower face was also found in the average group when protrusion degree rose to moderate protrusion from normal profile (P <0.05). A significant interaction between facial attractiveness and mandibular protrusion was found in the lower face duration (P = 0.020). The threshold point (the point of mandibular protrusion degree that evoked attention to the lower face) of the attractive facial background was higher than that of the unattractive background. Once evoked, the effect of mandibular protrusion of the attractive group tended to be stronger than that of the unattractive group, though without statistical difference. CONCLUSIONS: Eyes are the most salient area. The increasing degree of mandibular protrusion tends to draw attention to the lower face from other facial features. Background attractiveness can modify this behavior.

Optogenetic control of mesenchymal cell fate towards precise bone regeneration.

Rationale: Spatial-temporal control of cell fate in vivo is of great importance for regenerative medicine. Currently, there remain no practical strategies to tune cell-fate spatial-temporally. Optogenetics is a biological technique that widely used to control cell activity in genetically defined neurons in a spatiotemporal-specific manner by light. In this study, optogenetics was repurposed for precise bone tissue regeneration. Methods: Lhx8 and BMP2 genes, which are considered as the master genes for mesenchymal stem cell proliferation and differentiation respectively, were recombined into a customized optogenetic control system. In the system, Lhx8 was constitutively expressed, while BMP2 together with shLhx8 expression was driven by blue light. Results: As expected, blue light induced BMP2 expression and inactivated Lhx8 expression in cells infected with the optogenetic control system. Optogenetic control of BMP2 and Lhx8 expression inversely regulates MSC fate in vitro. By animal study, we found that blue light could fine-tune the regeneration in vivo. Blue light illumination significantly promotes bone regeneration when the scaffold was loaded with MSCs infected with adeno-Lhx8, GI-Gal4DBD, LOV-VP16, and BMP2-shLhx8. Conclusions: Together, our study revealed that optogenetic control of the master genes for mesenchymal stem cell proliferation and differentiation would be such a candidate strategy for precise regenerative medicine.