BMP signaling maintains auricular chondrocyte identity and prevents microtia development by inhibiting protein kinase A.

Elastic cartilage constitutes a major component of the external ear, which functions to guide sound to the middle and inner ears. Defects in auricle development cause congenital microtia, which affects hearing and appearance in patients. Mutations in several genes have been implicated in microtia development, yet, the pathogenesis of this disorder remains incompletely understood. Here, we show that Prrx1 genetically marks auricular chondrocytes in adult mice. Interestingly, BMP-Smad1/5/9 signaling in chondrocytes is increasingly activated from the proximal to distal segments of the ear, which is associated with a decrease in chondrocyte regenerative activity. Ablation of Bmpr1a in auricular chondrocytes led to chondrocyte atrophy and microtia development at the distal part. Transcriptome analysis revealed that Bmpr1a deficiency caused a switch from the chondrogenic program to the osteogenic program, accompanied by enhanced protein kinase A activation, likely through increased expression of Adcy5/8. Inhibition of PKA blocked chondrocyte-to-osteoblast transformation and microtia development. Moreover, analysis of single-cell RNA-seq of human microtia samples uncovered enriched gene expression in the PKA pathway and chondrocyte-to-osteoblast transformation process. These findings suggest that auricle cartilage is actively maintained by BMP signaling, which maintains chondrocyte identity by suppressing osteogenic differentiation.

Strong and tough polysaccharide organohydrogels for strain, humidity and temperature sensors.

To avoid the potential toxicity of monomer residues in synthetic polymer based organohydrogels, natural polysaccharide-based organohydrogels are expected to be used in multi-functional wearable sensory systems, but most of them have unsatisfactory stiffness, strength and fracture toughness. Herein, a cooking and soaking strategy is proposed to prepare novel natural polysaccharide-based organohydrogels possessing outstanding stiffness, strength, toughness, freezing resistance, heating resistance and long-term durability. The agar organohydrogel exhibits a fracture stress of 3.3 MPa, a Young's modulus of 2.26 MPa and a fracture toughness of 14.8 kJ m-2, the κ-carrageenan organohydrogel exhibits a fracture stress of 3.3 MPa, a Young's modulus of 4.34 MPa and a fracture toughness of 11.0 kJ m-2, and the gellan organohydrogel exhibits a fracture stress of 1.2 MPa, a Young's modulus of 2.81 MPa and a fracture toughness of 5.4 kJ m-2. Furthermore, the agar organohydrogels are assembled into multi-functional wearable sensors by introducing NaCl as a conducting agent exhibiting responses to strain (5-150%), temperature (-15 to 60 °C) and humidity (11-97%), and possessing exceptional multi-sensory capabilities. Therefore, the developed strategy has shown a new pathway towards strengthening polysaccharide-based organohydrogels with potential for application in wearable sensory systems.

Prrx1 marks stem cells for bone, white adipose tissue and dermis in adult mice.

Specialized connective tissues, including bone and adipose tissues, control various physiological activities, including mineral and energy homeostasis. However, the identity of stem cells maintaining these tissues throughout adulthood remains elusive. By conducting genetic lineage tracing and cell depletion experiments in newly generated knock-in Cre/CreERT2 lines, we show here that rare Prrx1-expressing cells act as stem cells for bone, white adipose tissue and dermis in adult mice, which are indispensable for the homeostasis and repair of these tissues. Single-cell profiling reveals the cycling and multipotent nature of Prrx1-expressing cells and the stemness of these cells is further validated by transplantation assays. Moreover, we identify the cell surface markers for Prrx1-expressing stem cells and show that the activities of these stem cells are regulated by Wnt signaling. These findings expand our knowledge of connective tissue homeostasis/regeneration and may help improve stem-cell-based therapies.

Reclamation in southern China: The early Chu's agriculture revealed by macro-plant remains from the Wanfunao site (ca. 1000-770 BCE).

The Wanfunao site was a large Chu settlement in Zhou Dynasty. It was located on an alluvial plain along the Yangtze River in the Yichang section. The region around the site comprised mountains, hills, and plains, which was a compatible environment for the cultivation of various crops. Previous studies have suggested that the middle and lower reaches of the Yangtze River are one of the most productive regions for rice cultivation. Besides rice, however, seven dryland crops have been found at the Wanfunao site: foxtail millet, broomcorn millet, wheat, barley, oat, buckwheat, and adzuki bean. Among them, foxtail millet and rice are most ubiquitous. The crop assemblage has revealed that the northern dryland crops, including those were newly adapted cereals such as foxtail millet, wheat, and barley, gradually dispersed southward and became a part of the diet along with rice. This can be attributed to southern Chinese inhabitants' reclamation of the hilly environment for agriculture. Although communities in southern China had cultivated rice on the plains for thousands of years, newly introduced dryland crops from north China adapted to mountainous environments better. The development of multi-cropping systems in southern China likely involved changes in agricultural ontology associated with the adaptation of northern crops in southern environments newly encountered. Additionally, the assemblage of foxtail millet grain/rice spikelet base in the site may have been used for livestock feeding. A wide range of landforms, compatible farming, and surplus agricultural products for husbandry may have been a part of the economic foundation that facilitated the rise of Chu.

Dual-modality Imaging of Angiogenesis in Unstable Atherosclerotic Plaques with VEGFR2-Targeted Upconversion Nanoprobes in vivo.

AIM: Angiogenesis plays a major role in atherosclerotic plaque development and instability. Our study aims to develop a novel optical and magnetic resonance (MR) dual-modality molecular imaging probe to early detect unstable plaques in vivo by targeting biomarkers of angiogenesis in murine models of atherosclerosis (AS). METHODS: Immunofluorescence and western blot were used to detect the expression of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in activated Human Umbilical Vein Endothelial Cells (HUVECs). After synthesis and identification of novel short peptide VRBP1-targeted VEGFR2, HUVECs were co-cultured with FITC-VRBP1 to test specific affinity of VRBP1. Then VRBP1-UCNPstargeting VEGFR2 were constructed by conjugating VRBP1 to the surface of NaGdF4:Yb,Er@NaGdF4 nanoparticles. The characterization of the nanoparticles was performed by transmission electron microscopy (TEM), distribution of size, hydrodynamic size, zeta potential, absorption spectra, emission spectra, imaging intensity of different concentrations, binding affinity and cytotoxicity of nanoprobes in vitro. The upconversion luminescence (UCL) and MR imaging were performed to identify unstable atherosclerotic plaque in ApoE-/- mice in vivo and ex vivo. Morphological staining was used to verify AS model and angiogenesis, and Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) was used to confirm accumulation of the nanoparticles after imaging. RESULTS: After induced by hypoxia and ox-LDL, the expression of VEGFR2 in activated HUVECs was enhanced. FITC-VRBP1 can specifically bind to the HUVECs. Characterization of the nanoparticles showed that particles size is uniform with a stable structure, specific optical and MR signal, good binding affinity to VEGFR2 and low cytotoxicity. In vivo and ex vivo UCL imaging and quantitative analysis revealed that distinctive optical signal was observed in the regions of left carotid common arteries (LCCAs) of AS group after injection of VRBP1-UCNPs. Higher signal intensity on T1-weighted MR imaging appeared in the LCCA wall of AS group after injection. The results of morphological staining demonstrated angiogenesis in the atherosclerotic plaques, Gd ions in LCCAs, aortic arch and renal arteries bifurcations detected by ICP-AES confirmed accumulation of the nanoparticles in plaque. CONCLUSIONS: We successfully design and synthesize a novel UCNPs using peptide VRBP1 targeting to VEGFR2. In vivo imaging demonstrates that VRBP1-UCNPs can be used to perform optical/MR dual-modality imaging targeting angiogenesis in plaques, which is a promising technique to early detect unstable atherosclerosis.

Easy fabrication of aminated graphene oxide functionalized magnetic nanocomposite for efficient preconcentration of phenolic acids prior to HPLC determination: Application in tea-derived wines.

In this study, aminated graphene oxide functionalized magnetic nanocomposite (AGMN) was facilely synthesized by one-pot hydrothermal approach and acted as the extraction phase of magnetic solid phase extraction (MSPE) of phenolic acids (PAs). Characterization results revealed that the AGMN possessed satisfying saturation magnetism and abundant functional groups. Under the optimal extraction parameters, the proposed AGMN/MSPE presented high enrichment capability to PAs. Sensitive and dependable method for measurement of PAs in wine was proposed by the combination of AGMN/MSPE and HPLC/DAD. Limits of detection and limits of quantification were in the ranges of 0.031-0.23 µg/L and 0.10-0.78 µg/L, respectively, and the RSDs for approach precision varied from 1.8% to 8.9%. Recoveries at low, medium and high fortified levels varied from 84.6% to 116%. The suggested method was used to quantify investigated PAs in ten kinds of Tieguanyin tea-derived wines, and found the contents of PAs in wines were related to the quality of tea-leaves and alcohol content.