Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as ...determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation.
Lockdown is an effective nonpharmaceutical intervention to reduce coronavirus disease 2019 (COVID-19) transmission, but it restricts daily activity. We aimed to investigate the impact of lockdown on ...pediatric body weight and body mass index (BMI).
The systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Four online databases (EMBASE, Medline, the Cochrane Library and CINAHL) were searched.
The pooled results showed that lockdown was associated with significant body weight gain (MD 2.67, 95% CI 2.12-3.23;
< 0.00001). The BMI of children with comorbidities or obesity did not change significantly. The BMI of general population was significantly higher during lockdown than before the pandemic (MD 0.94, 95% CI 0.32-1.56;
= 0.003). However, heterogeneity was high (I
= 84%). Among changes in weight classification, increases in the rates of obesity (OR 1.23, 95% CI 1.10-1.37;
= 0.0002) and overweight (OR 1.17, 95% CI 1.06-1.29;
= 0.001) were reported.
Our meta-analysis showed significant increases in body weight and BMI during lockdown among school-age children and adolescents. The prevalence of obesity and overweight also increased. The COVID-19 pandemic worsened the burden of childhood obesity.
Background Ovarian cancer (OC) is the most lethal gynecological cancer due to the recurrence of drug-resistance. Cancer initiating cells (CICs) are proposed to be responsible for the aggressiveness ...of OC. The rarity and difficulty of in vitro long-term cultivation of CICs challenge the development of CIC-targeting therapeutics. Reprogramming cancer cells into induced cancer initiating cell (iCICs) could be an approach to solve these. Several inducible CICs have been acquired by activating the expression of stemness genes in different cancer cells. However, few reports have demonstrated the feasibility in OC. Methods Patients with primary OC receiving surgery were enrolled. Tumor tissue were collected, and OCT4, SOX2, and NANOG expressions were assessed by immunohistochemistry (IHC) staining to investigate the association of stemness markers with overall survival (OS). An high-grade serous ovarian cancer (HGSOC) cell line, OVCAR-3 was reprogrammed by transducing Yamanaka four factors OCT4, SOX2, KLF4 and MYC (OSKM) to establish an iOCIC model, iOVCAR-3-OSKM. CIC characteristics of iOVCAR-3-OSKM were evaluated by RT-PCR, sphere formation assay and animal experiments. Drug-resistance and migration ability were accessed by dye-efflux activity assay, MTT assay and migration assay. Gene profile was presented through RNA-sequencing. Lineage differentiation ability and organoid culture were determined by in vitro differentiation assays. Results In OC patients, the co-expression of multiple stem-related transcription factors (OCT4, SOX2, and NANOG) was associated with worse OS. iOVCAR-3-OSKM cells generated by reprogramming successfully exhibited stemness characteristics with strong sphere-forming and tumorigenesis ability. iOVCAR-3-OSKM cells also showed malignant potential with higher drug resistance to chemodrug, Paclitaxel (PTX) and migration ability. iOVCAR-3-OSKM was maintainable and expandable on feeder-dependent culture condition, it also preserved ovarian lineage differentiation abilities, which could well differentiate into OC cells with CK-7 and CA125 expressions and develop into an organoid mimic poor prognostic OC histological feature. Conclusions The establishment of iOVCAR-3-OSKM not only allows us to fill the gap in the information on induced CICs in OC but also provides a potential strategy to develop personalized CICs and organoid models for treating OC in the near future. Keywords: Ovarian cancer (OC), Cancer-initiating cells (CICs), Induced ovarian cancer-initiating cells (iOCICs), Organoid and drug screening
Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is ...limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.
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After ischemic brain injury, many neurons die but surviving astrocytes become activated and proliferative. Using NeuroD1 AAV-based gene therapy, Chen and colleagues demonstrate robust neuroregeneration through direct astrocyte-to-neuron conversion and significantly improved functional recovery. This study provides a new paradigm for brain repair using in vivo cell conversion technology.
Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the ...evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA‐seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.
By single‐cell RNA sequencing and spatial transcriptomics, the early early‐disseminated breast cancer cells are found to travel from the border of primary tumor to axillary lymph nodes. During this metastasis, a switch between glycolysis and oxidative phosphorylation occurs in early disseminated breast cancer cells, indicating an interesting dynamic metabolic evolvement.
Molecular analysis of circulating tumor cells (CTCs) at single-cell resolution offers great promise for cancer diagnostics and therapeutics from simple liquid biopsy. Recent development of massively ...parallel single-cell RNA-sequencing (scRNA-seq) provides a powerful method to resolve the cellular heterogeneity from gene expression and pathway regulation analysis. However, the scarcity of CTCs and the massive contamination of blood cells limit the utility of currently available technologies. Here, we present Hydro-Seq, a scalable hydrodynamic scRNA-seq barcoding technique, for high-throughput CTC analysis. High cell-capture efficiency and contamination removal capability of Hydro-Seq enables successful scRNA-seq of 666 CTCs from 21 breast cancer patient samples at high throughput. We identify breast cancer drug targets for hormone and targeted therapies and tracked individual cells that express markers of cancer stem cells (CSCs) as well as of epithelial/mesenchymal cell state transitions. Transcriptome analysis of these cells provides insights into monitoring target therapeutics and processes underlying tumor metastasis.
Aculenes are a unique class of norsequiterpenes (C14) that are produced by Aspergillus aculeatus. The nordaucane skeleton in aculenes A–D may be derived from an ent‐daucane precursor through ...demethylation, however, the enzymes involved remain unexplored. We identified the biosynthetic gene cluster and characterized the biosynthetic pathway based on gene inactivation, feeding experiments, and heterologous reconstitution in Saccharomyces cerevisiae and Aspergillus oryzae. We discovered that three cytochrome P450 monoxygenases are required to catalyze the stepwise demethylation process. AneF converts the 12‐methyl group into a carboxylic acid and AneD installs the 10‐hydroxy group for later tautomerization and stabilization. Finally, AneG installs an electron‐withdrawing carbonyl group at the C‐2 position, which triggers C‐12 decarboxylation to yield the nordaucane skeleton. Additionally, a terpene cyclase (AneC) was found that forms a new product (dauca‐4,7‐diene).
Long time no C: Aculenes are a class of norsesquiterpenes (C14) that are derived from daucane sesquiterpenes (C15), but the biosynthetic basis of the demethylation remained unknown. Three novel P450 monooxygenases were discovered to catalyze a stepwise demethylation process, and a new ent‐daucane cyclase was also discovered. This work sheds light on how nature performs enzymatic demethylation and reveals new tools to expand chemical diversity.
Gold nanoparticles are popularly used in biological and chemical sensors and their applications owing to their fascinating chemical, optical, and catalytic properties. Particularly, the use of gold ...nanoparticles is widespread in colorimetric assays because of their simple, cost-effective fabrication, and ease of use. More importantly, the gold nanoparticle sensor response is a visual change in color, which allows easy interpretation of results. Therefore, many studies of gold nanoparticle-based colorimetric methods have been reported, and some review articles published over the past years. Most reviews focus exclusively on a single gold nanoparticle-based colorimetric technique for one analyte of interest. In this review, we focus on the current developments in different colorimetric assay designs for the sensing of various chemical and biological samples. We summarize and classify the sensing strategies and mechanism analyses of gold nanoparticle-based detection. Additionally, typical examples of recently developed gold nanoparticle-based colorimetric methods and their applications in the detection of various analytes are presented and discussed comprehensively.
ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47) of Arabidopsis thaliana is an AP2/ERF domain transcription factor that regulates jasmonate (JA) biosynthesis and is induced by ...methyl JA treatment. The regulatory mechanism of ORA47 remains unclear. ORA47 is shown to bind to the cis-element (NC/GT)CGNCCA, which is referred to as the O-box, in the promoter of ABI2. We proposed that ORA47 acts as a connection between ABA INSENSITIVE1 (ABI1) and ABI2 and mediates an ABI1–ORA47–ABI2 positive feedback loop.
PORA47:ORA47-GFP transgenic plants were used in a chromatin immunoprecipitation (ChIP) assay to show that ORA47 participates in the biosynthesis and/or signaling pathways of nine phytohormones. Specifically, many abscisic acid (ABA) and JA biosynthesis and signaling genes were direct targets of ORA47 under stress conditions.
The JA content of the P35S:ORA47-GR lines was highly induced under wounding and moderately induced under water stress relative to that of the wild-type plants. The wounding treatment moderately increased ABA accumulation in the transgenic lines, whereas the water stress treatment repressed the ABA content.
ORA47 is proposed to play a role in the biosynthesis of JA and ABA and in regulating the biosynthesis and/or signaling of a suite of phytohormone genes when plants are subjected to wounding and water stress.
The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell‐based model, we identified methylthioadenosine ...phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression‐free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP‐deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)‐mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl‐protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP‐deficient cells, lower sDMA modification prevents ubiquitination‐mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post‐translational regulation.
Synopsis
Repression of MTAP‐dependent symmetric dimethylation mediated by PRMT5 increases vimentin protein stability and leads to invasion and metastasis in MTAP‐deficient lung cancer.
MTAP loss promotes lung cancer metastasis.
MTA accumulation in MTAP‐deficient cancer cells inhibits PRMT5‐mediated symmetric dimethylation on arginine residues of vimentin.
Vimentin is destabilized by PRMT5‐mediated symmetric dimethylation.
Reduced dimethylation and stabilization of vimentin in MTAP‐deficient cancer cells contributes to invasion and metastasis.
Repression of MTAP‐dependent symmetric dimethylation mediated by PRMT5 increases vimentin protein stability and leads to invasion and metastasis in MTAP‐deficient lung cancer.
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