Rich-club organization of whole-brain spatio-temporal multilayer functional connectivity networks.

Objective: In this work, we propose a novel method for constructing whole-brain spatio-temporal multilayer functional connectivity networks (FCNs) and four innovative rich-club metrics. Methods: Spatio-temporal multilayer FCNs achieve a high-order representation of the spatio-temporal dynamic characteristics of brain networks by combining the sliding time window method with graph theory and hypergraph theory. The four proposed rich-club scales are based on the dynamic changes in rich-club node identity, providing a parameterized description of the topological dynamic characteristics of brain networks from both temporal and spatial perspectives. The proposed method was validated in three independent differential analysis experiments: male-female gender difference analysis, analysis of abnormality in patients with autism spectrum disorders (ASD), and individual difference analysis. Results: The proposed method yielded results consistent with previous relevant studies and revealed some innovative findings. For instance, the dynamic topological characteristics of specific white matter regions effectively reflected individual differences. The increased abnormality in internal functional connectivity within the basal ganglia may be a contributing factor to the occurrence of repetitive or restrictive behaviors in ASD patients. Conclusion: The proposed methodology provides an efficacious approach for constructing whole-brain spatio-temporal multilayer FCNs and conducting analysis of their dynamic topological structures. The dynamic topological characteristics of spatio-temporal multilayer FCNs may offer new insights into physiological variations and pathological abnormalities in neuroscience.

The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells.

The mechanisms by which bone marrow stromal cells (BMSCs) maintain multilineage potency in vitro remain elusive. To identify the transcriptional regulatory circuits that contribute to BMSC multipotency, we performed paired single-nucleus multiomics of the expansion of freshly isolated BMSCs and of BMSCs undergoing tri-lineage differentiation. By computationally reconstructing the regulatory programs associated with initial stages of differentiation and early expansion, we identified the TEAD family of transcription factors, which is inhibited by Hippo signaling, as highly active in the BMSC in vitro multipotent state. Pharmacological inhibition of TEAD enhanced BMSC osteogenic and adipogenic differentiation, whereas its activation maintained BMSCs in an undifferentiated state, supporting a model whereby isolation of BMSCs coincides with a TEAD-controlled transcriptional state linked to multipotency. Our study highlights the Hippo pathway as a pivotal regulator of BMSC multipotency, and our regulatory network inferences are a reservoir of testable hypotheses that link transcription factors and their regulons to specific aspects of BMSC behavior.

A Low-Cost AI Buoy System for Monitoring Water Quality at Offshore Aquaculture Cages.

The ocean resources have been rapidly depleted in the recent decade, and the complementary role of aquaculture to food security has become more critical than ever before. Water quality is one of the key factors in determining the success of aquaculture and real-time water quality monitoring is an important process for aquaculture. This paper proposes a low-cost and easy-to-build artificial intelligence (AI) buoy system that autonomously measures the related water quality data and instantly forwards them via wireless channels to the shore server. Furthermore, the data provide aquaculture staff with real-time water quality information and also assists server-side AI programs in implementing machine learning techniques to further provide short-term water quality predictions. In particular, we aim to provide a low-cost design by combining simple electronic devices and server-side AI programs for the proposed buoy system to measure water velocity. As a result, the cost for the practical implementation is approximately USD 2015 only to facilitate the proposed AI buoy system to measure the real-time data of dissolved oxygen, salinity, water temperature, and velocity. In addition, the AI buoy system also offers short-term estimations of water temperature and velocity, with mean square errors of 0.021 °C and 0.92 cm/s, respectively. Furthermore, we replaced the use of expensive current meters with a flow sensor tube of only USD 100 to measure water velocity.

Nano-oxygenated hydrogels for locally and permeably hypoxia relieving to heal chronic wounds.

Exposed chronic wounds are usually covered by hypoxic tissues accompanied with necrosis, persistent inflammation and anaerobic infections. Since atmospheric oxygen air can only penetrate about 0.3 mm tissues, meanwhile oxygen from the circulation is difficult to reach chronic wounds through the destroyed blood vessels, a solution to deliver oxygen locally and permeably is urgently needed. Herein we report a technique to reform traditional gel-based wound dressings by adding lyophilized oxygen encapsulated nanoparticles, which can deliver dissolved oxygen locally into wound surface. This delivery technique can potentially evaluate the therapeutic effects on hypoxic epithelial, endothelial and fibroblasts in vitro. Further experiments confirm the effects on both open wounds bearing and flap transplanted diabetic mice models. Considering its biocompatibility, effectiveness and practicality, we believe our hydrogel has significant transformation value to care and accelerate the healing of various clinical wounds, especially chronic wound.

Single-Cell Transcriptomic Census of Endothelial Changes Induced by Matrix Stiffness and the Association with Atherosclerosis.

Vascular endothelial cell (EC) plasticity plays a critical role in the progression of atherosclerosis by giving rise to mesenchymal phenotypes in the plaque lesion. Despite the evidence for arterial stiffening as a major contributor to atherosclerosis, the complex interplay among atherogenic stimuli in vivo has hindered attempts to determine the effects of extracellular matrix (ECM) stiffness on endothelial-mesenchymal transition (EndMT). To study the regulatory effects of ECM stiffness on EndMT, an in vitro model is developed in which human coronary artery ECs are cultured on physiological or pathological stiffness substrates. Leveraging single-cell RNA sequencing, cell clusters with mesenchymal transcriptional features are identified to be more prevalent on pathological substrates than physiological substrates. Trajectory inference analyses reveal a novel mesenchymal-to-endothelial reverse transition, which is blocked by pathological stiffness substrates, in addition to the expected EndMT trajectory. ECs pushed to a mesenchymal character by pathological stiffness substrates are enriched in transcriptional signatures of atherosclerotic ECs from human and murine plaques. This study characterizes at single-cell resolution the transcriptional programs that underpin EC plasticity in both physiological or pathological milieus, and thus serves as a valuable resource for more precisely defining EndMT and the transcriptional programs contributing to atherosclerosis.

Constructing novel hyper-crosslinked conjugated polymers through molecular expansion for enhanced gas adsorption performance.

The porous organic polymers have been considered as effective materials for gas storage and adsorption. Herein, we synthesized highly crystalline nitrogen-rich covalent triazine frameworks (CTFs) by polycondensation for preparing the novel hyper-cross-linked conjugated polymers (HCCPs) with tunable specific surface area and pore volume through coupling Friedel-Crafts reaction, in which 1,4-Bis(chloromethyl)benzene and 4,4-Bis(chloromethyl)biphenyl as the expansion molecules were pillared between the layers of CTF-HUST. This technology not only increased the specific surface area and total pore volume of CTF-HUST by 2.56 and 4.68 times, but also greatly enhanced the utilization of adsorption sites of CTF-HUST. The HCCP2-1.25 exhibited the highest surface area (1349.29 m2g-1) among these HCCPs and demonstrated excellent adsorption performance for ethyl acetate (1605.14 mg/g), ethanol (1371.49 mg/g), 1,2-Dichloroethane (1971.68 mg/g), benzene (1151.77 mg/g) and toluene (1024.28 mg/g) due to the multiple C-H…O, C-H…Cl, O-H…N and C-H…π interactions between volatile organic compounds (VOCs) and HCCPs framework. Moreover, CO2 and H2 storage capacities of the HCCP2-1.25 were 8.02 wt% and 1.54 wt%, 1.66 and 1.67 times higher than CTF-HUST, respectively. This study developed a simple and effective molecular expansion strategy to synthesize a series of novel high-surface-area porous polymers for potential applications in the environmental field.

Current Progress and Outlook of Nano-Based Hydrogel Dressings for Wound Healing.

Wound dressing is an important tool for wound management. Designing wound dressings by combining various novel materials and drugs to optimize the peri-wound environment and promote wound healing is a novel concept. Hydrogels feature good ductility, high water content, and favorable oxygen transport, which makes them become some of the most promising materials for wound dressings. In addition, nanomaterials exhibit superior biodegradability, biocompatibility, and colloidal stability in wound healing and can play a role in promoting healing through their nanoscale properties or as carriers of other drugs. By combining the advantages of both technologies, several outstanding and efficient wound dressings have been developed. In this paper, we classify nano-based hydrogel dressings into four categories: hydrogel dressings loaded with a nanoantibacterial drug; hydrogel dressings loaded with oxygen-delivering nanomedicines; hydrogel dressings loaded with nanonucleic acid drugs; and hydrogel dressings loaded with other nanodelivered drugs. The design ideas, advantages, and challenges of these nano-based hydrogel wound dressings are reviewed and analyzed. Finally, we envisaged possible future directions for wound dressings in the context of relevant scientific and technological advances, which we hope will inform further research in wound management.

Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGF-ß signaling.

The patterning and ossification of the mammalian skeleton requires the coordinated actions of both intrinsic bone morphogens and extrinsic neurovascular signals, which function in a temporal and spatial fashion to control mesenchymal progenitor cell (MPC) fate. Here, we show the genetic inhibition of tropomyosin receptor kinase A (TrkA) sensory nerve innervation of the developing cranium results in premature calvarial suture closure, associated with a decrease in suture MPC proliferation and increased mineralization. In vitro, axons from peripheral afferent neurons derived from dorsal root ganglions (DRGs) of wild-type mice induce MPC proliferation in a spatially restricted manner via a soluble factor when cocultured in microfluidic chambers. Comparative spatial transcriptomic analysis of the cranial sutures in vivo confirmed a positive association between sensory axons and proliferative MPCs. SpatialTime analysis across the developing suture revealed regional-specific alterations in bone morphogenetic protein (BMP) and TGF-ß signaling pathway transcripts in response to TrkA inhibition. RNA sequencing of DRG cell bodies, following direct, axonal coculture with MPCs, confirmed the alterations in BMP/TGF-ß signaling pathway transcripts. Among these, the BMP inhibitor follistatin-like 1 (FSTL1) replicated key features of the neural-to-bone influence, including mitogenic and anti-osteogenic effects via the inhibition of BMP/TGF-ß signaling. Taken together, our results demonstrate that sensory nerve-derived signals, including FSTL1, function to coordinate cranial bone patterning by regulating MPC proliferation and differentiation in the suture mesenchyme.

Transcriptomic alterations underline aging of osteogenic bone marrow stromal cells.

BACKGROUND: Multipotent bone marrow stromal cells (BMSCs) are adult stem cells that form functional osteoblasts and play a critical role in bone remodeling. During aging, an increase in bone loss and reduction in structural integrity lead to osteoporosis and result in an increased risk of fracture. We examined age-dependent histological changes in murine vertebrae and uncovered that bone loss begins as early as the age of 1 mo. AIM: To identify the functional alterations and transcriptomic dynamics of BMSCs during early bone loss. METHODS: We collected BMSCs from mice at early to middle ages and compared their self-renewal and differentiation potential. Subsequently, we obtained the transcriptomic profiles of BMSCs at 1 mo, 3 mo, and 7 mo. RESULTS: The colony-forming and osteogenic commitment capacity showed a comparable finding that decreased at the age of 1 mo. The transcriptomic analysis showed the enrichment of osteoblastic regulation genes at 1 mo and loss of osteogenic features at 3 mo. The BMSCs at 7 mo showed enrichment of adipogenic and DNA repair features. Moreover, we demonstrated that the WNT and MAPK signaling pathways were upregulated at 1 mo, followed by increased pro-inflammatory and apoptotic features. CONCLUSION: Our study uncovered the cellular and molecular dynamics of bone aging in mice and demonstrated the contribution of BMSCs to the early stage of age-related bone loss.

Novel Lineage-Tracing System to Identify Site-Specific Ectopic Bone Precursor Cells.

Heterotopic ossification (HO) is a form of pathological cell-fate change of mesenchymal stem/precursor cells (MSCs) that occurs following traumatic injury, limiting range of motion in extremities and causing pain. MSCs have been shown to differentiate to form bone; however, their lineage and aberrant processes after trauma are not well understood. Utilizing a well-established mouse HO model and inducible lineage-tracing mouse (Hoxa11-CreERT2;ROSA26-LSL-TdTomato), we found that Hoxa11-lineage cells represent HO progenitors specifically in the zeugopod. Bioinformatic single-cell transcriptomic and epigenomic analyses showed Hoxa11-lineage cells are regionally restricted mesenchymal cells that, after injury, gain the potential to undergo differentiation toward chondrocytes, osteoblasts, and adipocytes. This study identifies Hoxa11-lineage cells as zeugopod-specific ectopic bone progenitors and elucidates the fate specification and multipotency that mesenchymal cells acquire after injury. Furthermore, this highlights homeobox patterning genes as useful tools to trace region-specific progenitors and enable location-specific gene deletion.

A single cell transcriptional atlas of early synovial joint development.

Synovial joint development begins with the formation of the interzone, a region of condensed mesenchymal cells at the site of the prospective joint. Recently, lineage-tracing strategies have revealed that Gdf5-lineage cells native to and from outside the interzone contribute to most, if not all, of the major joint components. However, there is limited knowledge of the specific transcriptional and signaling programs that regulate interzone formation and fate diversification of synovial joint constituents. To address this, we have performed single cell RNA-Seq analysis of 7329 synovial joint progenitor cells from the developing murine knee joint from E12.5 to E15.5. By using a combination of computational analytics, in situ hybridization and in vitro characterization of prospectively isolated populations, we have identified the transcriptional profiles of the major developmental paths for joint progenitors. Our freely available single cell transcriptional atlas will serve as a resource for the community to uncover transcriptional programs and cell interactions that regulate synovial joint development.

Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes.

Chronic wounds in diabetes undergo a lifetime risk of developing into diabetic foot ulcers. Oxygen is crucial to wound healing by regulating cell proliferation, migration, and neovascularization. However, current oxygen therapies, including hyperbaric oxygen (HBO) and topical gaseous oxygen (TGO), mainly employ gaseous oxygen delivery, which is much less effective in penetrating the skin. Here, we introduce an oxygen-producing patch, made of living microalgae hydrogel, which can produce dissolved oxygen. The superior performance of the patch that results from its dissolved oxygen delivery is >100-fold much more efficient than TGO penetrating the skin. Further experiments indicate that the patch could promote cell proliferation, migration, and tube formation in vitro, and improve chronic wound healing and the survival of skin grafts in diabetic mice. We believe that the microalgae-gel patch can provide continuous dissolved oxygen to improve chronic wound healing.

Small molecules for mesenchymal stem cell fate determination.

Mesenchymal stem cells (MSCs) are adult stem cells harboring self-renewal and multilineage differentiation potential that are capable of differentiating into osteoblasts, adipocytes, or chondrocytes in vitro, and regulating the bone marrow microenvironment and adipose tissue remodeling in vivo. The process of fate determination is initiated by signaling molecules that drive MSCs into a specific lineage. Impairment of MSC fate determination leads to different bone and adipose tissue-related diseases, including aging, osteoporosis, and insulin resistance. Much progress has been made in recent years in discovering small molecules and their underlying mechanisms control the cell fate of MSCs both in vitro and in vivo. In this review, we summarize recent findings in applying small molecules to the trilineage commitment of MSCs, for instance, genistein, medicarpin, and icariin for the osteogenic cell fate commitment; isorhamnetin, risedronate, and arctigenin for pro-adipogenesis; and atractylenolides and dihydroartemisinin for chondrogenic fate determination. We highlight the underlying mechanisms, including direct regulation, epigenetic modification, and post-translational modification of signaling molecules in the AMPK, MAPK, Notch, PI3K/AKT, Hedgehog signaling pathways etc. and discuss the small molecules that are currently being studied in clinical trials. The target-based manipulation of lineage-specific commitment by small molecules offers substantial insights into bone marrow microenvironment regulation, adipose tissue homeostasis, and therapeutic strategies for MSC-related diseases.

Ligustrazine Prevents Intervertebral Disc Degeneration via Suppression of Aberrant TGFß Activation in Nucleus Pulposus Cells.

OBJECTIVES: Aberrant transforming growth factor ß (TGFß) activation is detrimental to both nucleus pulposus (NP) cells and cartilage endplates (CEPs), which can lead to intervertebral disc degeneration (IDD). Ligustrazine (LIG) reduces the expression of inflammatory factors and TGFß1 in hypertrophic CEP to prevent IDD. In this study, we investigate the effects of LIG on NP cells and the TGFß signaling. DESIGN: LIG was injected to the lumbar spinal instability (LSI) mouse model. The effect of LIG was evaluated by intervertebral disc (IVD) score in the LSI mouse model. The expression of activated TGFß was examined using immunostaining with pSmad2/3 antibody. The upright posture (UP) rat model was also treated and evaluated in the same manner to assess the effect of LIG. In ex vivo study, IVDs from four-week old mice were isolated and treated with 10-5, 10-6, and 10-7 M of LIG. We used western blot to detect activated TGFß expression. TGFß-treated human nucleus pulposus cells (HNPCs) were cotreated with optimized dose of LIG in vitro. Immunofluorescence staining was performed to determine pSmad2/3, connective tissue growth factor (CCN2), and aggrecan (ACAN) expression levels. RESULTS: IVD score and the percentage of pSmad2/3+ NP cells were low in LIG-treated LSI mice in comparison with LSI mice, but close to the levels in the Sham group. Similarly, LIG reduced the overexpression of TGFß1 in NP cells. The inhibitory effect of LIG was dose dependent. A dose of 10-5 M LIG not only strongly attenuated Smad2/3 phosphorylation in TGFß-treated IVD ex vivo but also suppressed pSmad2/3, CCN2, and ACAN expression in TGFß-treated NP cells in vitro. CONCLUSIONS: LIG prevents IDD via suppression of TGFß overactivation in NP cells.

Perfluorocarbon regulates the intratumoural environment to enhance hypoxia-based agent efficacy.

Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective. To solve this problem, herein, we report that perfluorocarbon nanoparticles (PNPs) can be used to create a long-lasting, penetrable and hypoxic tumour microenvironment for ensuring both the delivery and activation of subsequently administered HBAs. In addition to the increased permeability and enhanced hypoxia caused by the PNPs, the PNPs can be retained to further achieve the long-term inhibition of intratumoural O2 reperfusion while enhancing HBA accumulation for over 24 h. Therefore, perfluorocarbon materials may have great potential for reigniting clinical research on hypoxia-based drugs.

Fractal superconducting nanowire single-photon detectors with reduced polarization sensitivity.

We demonstrate superconducting nanowire single-photon detectors (SNSPDs) based on a fractal design of the nanowires to reduce the polarization sensitivity of detection efficiency. We patterned niobium titanium nitride thin films into Peano curves with a linewidth of 100 nm and integrated the nanowires with optical microcavities to enhance their optical absorption. At a base temperature of 2.6 K, the fractal SNSPD exhibited a polarization-maximum device efficiency of 67% and a polarization-minimum device efficiency of 61% at a wavelength of 1550 nm. Therefore, the polarization sensitivity, defined as their ratio, was 1.1, lower than the polarization sensitivity of the SNSPDs in the meander design. The reduced polarization sensitivity of the detector could be maintained for higher-order spatial modes in multimode optical fibers and could tolerate misalignment between the optical mode and the detector. This fractal design is applicable to both amorphous and polycrystalline materials that are commonly used for making SNSPDs.

Gene expression profiling in prognosis of distant recurrence in HR-positive and HER2-negative breast cancer patients.

There had been several studies using gene-expression profiling in predicting distant recurrence in breast cancer. In this study, we developed an 18-gene classifier (18-GC) to predict distant recurrence of breast cancer and compared it with the 21-gene panel (Oncotype DX®, ODx) in performance. Included were 224 breast cancer patients with positive hormonal receptor (HR+) and negative human epidermal growth factor receptor 2 (HER2-). We compared the demographic, clinical, and survival information of the patients, and further compared the prediction of recurrence risk obtained by using the 18-GC with that by ODx. To have the best combined sensitivity and specificity, receiver operating characteristics (ROC) curve analysis was performed to determine the cutoff values for several breakpoint scores. For the new 18-GC, a breakpoint score of 21 was adopted to produce a combined highest sensitivity (95%) and specificity (39%) in detecting distant recurrence. At this breakpoint score, 164 of the 224 patients were classified by the 18-GC in the same risk level as by ODx, giving a concordance rate of 73%. Along with patient age and tumor stage, this 18-GC was found to be an independent significant prognostic factor of distant metastasis of breast cancer. We have thus created a new gene panel assay for prediction of distant recurrence in HR+ and HER2- breast cancer patients. With a high concordance rate with ODx, this new assay may serve as a good tool for individual breast cancer patients to make an informed decision on whether adjuvant chemotherapy should be performed post-surgery.

Validation of the 18-gene classifier as a prognostic biomarker of distant metastasis in breast cancer.

We validated an 18-gene classifier (GC) initially developed to predict local/regional recurrence after mastectomy in estimating distant metastasis risk. The 18-gene scoring algorithm defines scores as: <21, low risk; ≥21, high risk. Six hundred eighty-three patients with primary operable breast cancer and fresh frozen tumor tissues available were included. The primary outcome was the 5-year probability of freedom from distant metastasis (DMFP). Two external datasets were used to test the predictive accuracy of 18-GC. The 5-year rates of DMFP for patients classified as low-risk (n = 146, 21.7%) and high-risk (n = 537, 78.6%) were 96.2% (95% CI, 91.1%-98.8%) and 80.9% (74.6%-81.9%), respectively (median follow-up interval, 71.8 months). The 5-year rates of DMFP of the low-risk group in stage I (n = 62, 35.6%), stage II (n = 66, 20.1%), and stage III (n = 18, 10.3%) were 100%, 94.2% (78.5%-98.5%), and 90.9% (50.8%-98.7%), respectively. Multivariate analysis revealed that 18-GC is an independent prognostic factor of distant metastasis (adjusted hazard ratio, 5.1; 95% CI, 1.8-14.1; p = 0.0017) for scores of ≥21. External validation showed that the 5-year rate of DMFP in the low- and high-risk patients was 94.1% (82.9%-100%) and 80.3% (70.7%-89.9%, p = 0.06) in a Singapore dataset, and 89.5% (81.9%-94.1%) and 73.6% (67.2%-79.0%, p = 0.0039) in the GEO-GSE20685 dataset, respectively. In conclusion, 18-GC is a viable prognostic biomarker for breast cancer to estimate distant metastasis risk.

The role of adhesions between homologous cancer cells in tumor progression and targeted therapy.

INTRODUCTION: Adhesions between homologous cancer cells play an important role in promoting tumor progression and designing tumor-targeting methods. Known as 'homologous adhesions' of cancerous cells, these are usually more specific than adhesions to normal cells and heterogenic cells, and they have been widely discovered both in vivo and in vitro. The aberrant expression of cell adhesion-related molecules (CARMs) on each species of cancer cells is mainly responsible for inducing more specific homologous adhesions. Based on the improvement of biomimetic technologies, such adhesion has been investigated and applied deeply in drug delivery systems recently. Areas covered: This review focuses on the discovery, mechanism and application of homologous adhesion and aims to assist researchers with a clear understanding for more effective development. The advantages and challenges of recent research progress and therapeutic applications are also described and discussed. Expert commentary: Homologous adhesion shows promise in providing new strategies for targeted drug delivery and tailored cancer treatments. However, the 'homing' property of certain cancer cell types remains unclear and needs to be further defined.

Overcome the limitation of hypoxia against photodynamic therapy to treat cancer cells by using perfluorocarbon nanodroplet for photosensitizer delivery.

The low oxygen concentration limits the therapeutic efficacy of photodynamic therapy in treating cancer cells in hypoxia, since the cytotoxic 1O2 can't be effectively generated in this condition. To overcome this, we load photosensitizer into perfluorocarbon nanodroplet, which has a high oxygen capacity to enrich O2 for photodynamic consumption. Under the well-controlled hypoxic condition, we test its efficacy both in vitro and in vivo. This method can be successfully used for destroying cancer cells in hypoxic condition.