Plastic footprint deteriorates dryland carbon footprint across soil-plant-atmosphere continuum.

Plastic fragments are widely found in the soil profile of terrestrial ecosystems, forming plastic footprint and posing increasing threat to soil functionality and carbon (C) footprint. It is unclear how plastic footprint affects C cycling, and in particularly permanent C sequestration. Integrated field observations (including 13C labelling) were made using polyethylene and polylactic acid plastic fragments (low-, medium- and high-concentrations as intensifying footprint) landfilling in soil, to track C flow along soil-plant-atmosphere continuum (SPAC). The result indicated that increased plastic fragments substantially reduced photosynthetic C assimilation (p < 0.05), regardless of fragment degradability. Besides reducing C sink strength, relative intensity of C emission increased significantly, displaying elevated C source. Moreover, root C fixation declined significantly from 21.95 to 19.2 mg m-2, and simultaneously root length density, root weight density, specific root length and root diameter and surface area were clearly reduced. Similar trends were observed in the two types of plastic fragments (p > 0.05). Particularly, soil aggregate stability was significantly lowered as affected by plastic fragments, which accelerated the decomposition rate of newly sequestered C (p < 0.05). More importantly, net C rhizodeposition declined averagely from 39.77 to 29.41 mg m-2, which directly led to significant decline of permanent C sequestration in soil. Therefore, increasing plastic footprint considerably worsened C footprint regardless of polythene and biodegradable fragments. The findings unveiled the serious effects of plastic residues on permanent C sequestration across SPAC, implying that current C assessment methods clearly overlook plastic footprint and their global impact effects.

High quality repair of osteochondral defects in rats using the extracellular matrix of antler stem cells.

BACKGROUND: Cartilage defects are some of the most common causes of arthritis. Cartilage lesions caused by inflammation, trauma or degenerative disease normally result in osteochondral defects. Previous studies have shown that decellularized extracellular matrix (ECM) derived from autologous, allogenic, or xenogeneic mesenchymal stromal cells (MSCs) can effectively restore osteochondral integrity. AIM: To determine whether the decellularized ECM of antler reserve mesenchymal cells (RMCs), a xenogeneic material from antler stem cells, is superior to the currently available treatments for osteochondral defects. METHODS: We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70% confluence; 50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition. Decellularized sheets of adipocyte-derived MSCs (aMSCs) and antlerogenic periosteal cells (another type of antler stem cells) were used as the controls. Three weeks after ascorbic acid stimulation, the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints. RESULTS: The defects were successfully repaired by applying the ECM-sheets. The highest quality of repair was achieved in the RMC-ECM group both in vitro (including cell attachment and proliferation), and in vivo (including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues). Notably, the antler-stem-cell-derived ECM (xenogeneic) performed better than the aMSC-ECM (allogenic), while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells. CONCLUSION: Decellularized xenogeneic ECM derived from the antler stem cell, particularly the active form (RMC-ECM), can achieve high quality repair/reconstruction of osteochondral defects, suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.

Intravitreal injection of conbercept for diabetic macular edema complicated with diabetic nephropathy.

AIM: To observe the therapeutic effect of conbercept on diabetic macular edema (DME) complicated with diabetic nephropathy (DN). METHODS: In this retrospective study, 54 patients (54 eyes) that diagnosed as DME from January 2017 to October 2021 were collected. The patients were divided into two groups: DME patients with DN (25 eyes), and DME patients without DN (29 eyes). General conditions were collected before treatment, laboratory tests include fasting blood glucose, HbA1c, microalbumin/creatinine, serum creatinine. Optical coherence tomography (OCT) was used to check the ellipsoidal zone (EZ) and external limiting membrane (ELM) integrity. Central macular thickness (CMT), best corrected visual acuity (BCVA), and retinal hyperreflective foci (HF) as well as numbers of injections were recorded. RESULTS: There were significant differences between fasting blood glucose, HbA1c, serum creatinine, urinary microalbumin/creatinine, and estimated glomerular filtration rate (eGFR) between the two groups (all P<0.05). EZ and ELM continuity in the DME+DN group was worse than that in the DME group (P<0.05). BCVA (logMAR) in the DME group was significantly better than that in the DME+DN group at the same time points during treatment (all P<0.05). CMT and HF values were significantly higher in the DME+DN group than that in the DME group at the all time points (all P<0.05) and significantly decreased in both groups with time during treatment. At 6mo after treatment, the mean number of injections in the DME+DN and DME group was 4.84±0.94 and 3.79±0.86, respectively. CONCLUSION: Conbercept has a significant effect in short-term treatment of DME patients with or without DN, and can significantly ameliorate BCVA, CMT and the number of HF, treatment efficacy of DME patients without DN is better than that of DME patients with DN.

Artificial Intelligence-based database for prediction of protein structure and their alterations in ocular diseases.

The aim of the study is to establish an online database for predicting protein structures altered in ocular diseases by Alphafold2 and RoseTTAFold algorithms. Totally, 726 genes of multiple ocular diseases were collected for protein structure prediction. Both Alphafold2 and RoseTTAFold algorithms were built locally using the open-source codebases. A dataset with 48 protein structures from Protein Data Bank (PDB) was adopted for algorithm set-up validation. A website was built to match ocular genes with the corresponding predicted tertiary protein structures for each amino acid sequence. The predicted local distance difference test-Cα (pLDDT) and template modeling (TM) scores of the validation protein structure and the selected ocular genes were evaluated. Molecular dynamics and molecular docking simulations were performed to demonstrate the applications of the predicted structures. For the validation dataset, 70.8% of the predicted protein structures showed pLDDT greater than 90. Compared to the PDB structures, 100% of the AlphaFold2-predicted structures and 97.9% of the RoseTTAFold-predicted structure showed TM score greater than 0.5. Totally, 1329 amino acid sequences of 430 ocular disease-related genes have been predicted, of which 75.9% showed pLDDT greater than 70 for the wildtype sequences and 76.1% for the variant sequences. Small molecule docking and molecular dynamics simulations revealed that the predicted protein structures with higher confidence scores showed similar molecular characteristics with the structures from PDB. We have developed an ocular protein structure database (EyeProdb) for ocular disease, which is released for the public and will facilitate the biological investigations and structure-based drug development for ocular diseases. Database URL:  http://eyeprodb.jsiec.org.

Microplastics affect soil bacterial community assembly more by their shapes rather than the concentrations.

Polyethylene film mulching is a key technology for soil water retention in dryland agriculture, but the aging of the films can generate a large number of microplastics with different shapes. There exists a widespread misunderstanding that the concentrations of microplastics might be the determinant affecting the diversity and assembly of soil bacterial communities, rather than their shapes. Here, we examined the variations of soil bacteria community composition and functioning under two-year field incubation by four shapes (ball, fiber, fragment and powder) of microplastics along the concentration gradients (0.01%, 0.1% and 1%). Data showed that specific surface area of microplastics was significantly positively correlated with the variations of bacterial community abundance and diversity (r=0.505, p<0.05). The fragment- and fiber-shape microplastics displayed more pronounced interfacial continuity with soil particles and induced greater soil bacterial α-diversity, relative to the powder- and ball-shape ones. Strikingly, microplastic concentrations were not significantly correlated with bacterial community indices (r=0.079, p>0.05). Based on the variations of the ßNTI, bacterial community assembly actually followed both stochastic and deterministic processes, and microplastic shapes significantly modified soil biogeochemical cycle and ecological functions. Therefore, the shapes of microplastics, rather than the concentration, significantly affected soil bacterial community assembly, in association with microplastic-soil-water interfaces.

Plant biomass mediates the decomposition of polythene film-sourced pollutants in soil through plastisphere bacteria island effect.

The polyethylene (PE) film mulching as a water conservation technology has been widely used in dryland agriculture, yet the long-term mulching has led to increasing accumulation of secondary pollutants in soils. The decomposition of PE film-sourced pollutants is directly associated with the enrichment of specific bacterial communities. We therefore hypothesized that plant biomass may act as an organic media to mediate the pollutant decomposition via reshaping bacterial communities. To validate this hypothesis, plant biomass (dried maize straw and living clover) was embedded at the underlying surface of PE film, to track the changes in the composition and function of bacterial communities in maize field across two years. The results indicated that both dry crop straw and alive clover massively promoted the α-diversity and abundance of dominant bacteria at plastisphere, relative to bulk soil. Bacterial communities tended to be clustered at plastisphere, forming the bacteria islands to enrich pollutant-degrading bacteria, such as Sphingobacterium, Arthrobacter and Paracoccus. As such, plastisphere bacteria islands substantially enhanced the degradation potential of chloroalkene and benzoate (p < 0.05). Simultaneously, bacterial network became stabilized and congregated at plastisphere, and markedly improved the abundance of plastisphere module hubs and connectors bacteria via stochastic process. Particularly, bacterial community composition and plastic film-sourced pollutants metabolism were evidently affected by soil pH, carbon and nitrogen sources that were mainly derived from the embedded biomass. To sum up, plant biomass embedding as a nature-based strategy (NbS) can positively mediate the decomposition of plastic-sourced pollutants through plastisphere bacteria island effects.

Priming effects of nZVI on carbon sequestration and iron uptake are positively mediated by AM fungus in semiarid agricultural soils.

We investigated the priming effect of nanoscale zero-valent iron (nZVI) on carbon sink and iron uptake, and the possible mediation by AMF (arbuscular mycorrhizal fungi, Funneliformis mosseae) in semiarid agricultural soils. Maize seed dressings comprised of three nZVI concentrations of 0, 1, 2 g·kg-1 and was tested with and without AMF inoculation under high and low soil moistures, respectively. The ICP-OES observations indicated that both low dose of nZVI (1 g·kg-1) and high dose of nZVI (2 g·kg-1) significantly increased the iron concentrations in roots (L: 54.5-109.8 %; H: 119.1-245.4 %) and shoots (L: 40.8-78.9 %; H: 81.1-99.4 %). Importantly, the absorption and translocation rate of iron were substantially improved by AMF inoculation under the low-dose nZVI. Yet, the excess nanoparticles as a stress were efficiently relieved by rhizosphere hyphae, and the iron concentration in leaves and stems can maintain as high as about 300 mg·kg-1 while the iron translocation efficiency was reduced. Moreover, next-generation sequencing confirmed that appropriate amount of nZVI clearly improved the rhizosphere colonization of Funneliformis mosseae (p < 0.001) and the development of soil fungal community. Soil observations further showed that the hyphae development and GRSP (glomalin-related soil protein) secretion were significantly promoted (p < 0.05), with the increased R0.25 (< 0.25 mm) by 35.97-41.16 %. As a return, AMF and host plant turned to input more organic matter into soils for microbial growth and Fe uptake, and such interactions became more pronounced under drought stress. In contrast, high dose of nZVI (2 g·kg-1) tended to agglomerate on the surface of hyphae and spores, causing severe deformation and inactivation of AMF symbionts. Therefore, the priming effects of nZVI on carbon sequestration and Fe uptake in agricultural soils were positively mediated by AMF via the feedback loop of the plant-soil-microbe system for enhanced adaptation to global climate change.

Thickness effects of polyethylene and biodegradable film residuals on soil properties and dryland maize productivity.

Plastic film residuals are increasingly remaining in cultivated lands. However, it is a critical issue how residual plastic type and thickness affect soil properties and crop yield. To address this issue, in situ landfill was conducted using thick polyethylene (PEt1), thin polyethylene (PEt2), thick biodegradable (BIOt1), thin biodegradable (BIOt2) residues, and CK (control) with no residues landfill in a semiarid maize field. The findings demonstrated that the impact of various treatments on soil characteristics and maize yield varied considerably. Soil water content decreased by 24.82% in PEt1 and 25.43% in PEt2, compared to BIOt1 and BIOt2, respectively. BIOt2 treatment increased soil bulk density by 1.31 g cm-3 and lowered soil porosity by 51.11%, respectively; it also elevated the silt/clay proportion by 49.42% relative to CK. In contrast, microaggregate composition in PEt2 was higher (43.02%). Moreover, BIOt2 lowered soil nitrate (NO3-) and ammonium (NH4+) content. Compared with other treatments, BIOt2 resulted in significantly higher soil total nitrogen (STN) and lower SOC/STN. Finally, BIOt2 exhibited the lowest water use efficiency (WUE) (20.57 kg ha-1 mm-1) and yield (6896 kg ha-1) among all the treatments. Therefore, BIO film residues exhibited detrimental impacts on soil quality and maize productivity compared to PE film ones. Considering film thickness, thin residual films more evidently influenced soil quality and maize productivity than thick film ones.

Thickness-dependent release of microplastics and phthalic acid esters from polythene and biodegradable residual films in agricultural soils and its related productivity effects.

It is crucial to elucidate the release rate of microplastics (MPs) and phthalic acid esters (PAEs) in agricultural soil and their effects on crop productivity regarding film types and thicknesses. To address this issue, two-year landfill test was performed using 0.016 mm-thick polyethylene (PEt1) & biodegradable (BIOt1), and 0.01 mm-thin polyethylene (PEt2) & biodegradable (BIOt2) residual films as materials with no landfill as CK. Scanning electron microscopy (SEM) and infrared analyses revealed that two-year landfill caused considerable changes in physical forms and spectral peaks in BIO film, which was more pronounced in thin BIO (36.90 % weight loss). Yet, less changes were presented in the above analyzes in polyethylene (PE) films, and thick films damaged relatively less. MPs number was 86,829.11 n/kg in BIOt1 and 134,912.27 n/kg in BIOt2, equivalent to 2.55 and 3.72 times higher than in PEt1 and PEt2, respectively. This was closely associated with PAEs release, as soil PAEs concentration was substantially lower in PEt1 (17.60 g/kg) and PEt2 (21.43 g/kg) than in BIOt1 and BIOt2 (37.12 g/kg and 49.20 g/kg), respectively. Furthermore, maize productivity parameters were negatively correlated with the amount of MPs and PAEs. BIOt2 and PEt1 had the lowest and highest grain yield, respectively. BIO exhibited greater environmental risk and adverse effects on soil and crop productivity than PE film due to physical degradation and release of PAEs. Thickness-wise comparison exhibited that thin film residues had more adverse effect relative to thick film ones.

Evaluation of Myocilin Variant Protein Structures Modeled by AlphaFold2.

Deep neural network-based programs can be applied to protein structure modeling by inputting amino acid sequences. Here, we aimed to evaluate the AlphaFold2-modeled myocilin wild-type and variant protein structures and compare to the experimentally determined protein structures. Molecular dynamic and ligand binding properties of the experimentally determined and AlphaFold2-modeled protein structures were also analyzed. AlphaFold2-modeled myocilin variant protein structures showed high similarities in overall structure to the experimentally determined mutant protein structures, but the orientations and geometries of amino acid side chains were slightly different. The olfactomedin-like domain of the modeled missense variant protein structures showed fewer folding changes than the nonsense variant when compared to the predicted wild-type protein structure. Differences were also observed in molecular dynamics and ligand binding sites between the AlphaFold2-modeled and experimentally determined structures as well as between the wild-type and variant structures. In summary, the folding of the AlphaFold2-modeled MYOC variant protein structures could be similar to that determined by the experiments but with differences in amino acid side chain orientations and geometries. Careful comparisons with experimentally determined structures are needed before the applications of the in silico modeled variant protein structures.

High levels of TIMP1 are associated with increased extracellular matrix stiffness in isocitrate dehydrogenase 1-wild type gliomas.

Glioma progression is accompanied with increased tumor tissue stiffness, yet the underlying mechanisms are unclear. Herein, we employed atomic force microscopy analysis to show that tissue stiffness was higher in isocitrate dehydrogenase (IDH)-wild type gliomas than IDH-mutant gliomas. Bioinformatic analyses revealed that tissue inhibitor of metalloproteinase-1 (TIMP1) was one of the preferentially upregulated genes in IDH-wild type gliomas as compared to IDH-mutant gliomas, and its higher expression indicated worse prognosis of glioma patients. TIMP1 intensity determined by immunofluorescence staining on glioma tissues positively correlated with glioma tissue stiffness. Mechanistically, TIMP1 expression was positively correlated with the gene expression of two predominant extracellular matrix components, tenascin C and fibronectin, both of which were also highly expressed in IDH-wild type gliomas. By introducing IDH1-R132H-containing vectors into human IDH1-wild type glioma cells to obtain an IDH1-mutant cell line, we found that IDH1 mutation increased the TIMP1 promoter methylation through methylation-specific PCR. More importantly, IDH1-R132H mutation decreased both the expression of TIMP1, fibronectin, tenascin C, and the tumor tissue stiffness in IDH1-mutant glioma xenografts in contrast to IDH1-wild type counterparts. Moreover, TIMP1 knockdown in IDH-wild type glioma cells inhibited the expression of tenascin C and fibronectin, and decreased tissue stiffness in intracranial glioma xenografts. Conclusively, we revealed an IDH mutation status-mediated mechanism in regulating glioma tissue stiffness through modulating TIMP1 and downstream extracellular matrix components.

PLXDC2 enhances invadopodium formation to promote invasion and metastasis of gastric cancer cells via interacting with PTP1B.

Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. In this study, we found that PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients' outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 enhanced the level of phosphorylated Cortactin (p-Cortactin) by physically interacting with protein tyrosine phosphatase 1B (PTP1B), an important dephosphorylase, to prevent its dephosphorylating of p-Cortactin, thereby promoting the formation of invadopodia. Collectively, our results indicate that PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.

A map of the spatial distribution and tumour-associated macrophage states in glioblastoma and grade 4 IDH-mutant astrocytoma.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

Dicer deficiency impairs proliferation but potentiates anti-tumoral effect of macrophages in glioblastoma.

Glioblastoma is a lethal primary brain tumor with abundant immune-suppressive glioblastoma-associated macrophage (GAM) infiltration. Skewing immune suppressive GAMs towards an immune-activating phenotype represents a promising immunotherapeutic strategy against glioblastoma. Herein, we reported that genetic deletion of miRNA-processing enzyme Dicer in macrophages inhibited the growth of GL261 murine glioblastoma xenografts and prolonged survival of tumor-bearing mice. Single cell RNA sequencing (scRNA-seq) of the tumor-infiltrating immune cells revealed that Dicer deletion in macrophages reduced the proportion of cell-cycling GAM cluster and reprogramed the remaining GAMs towards a proinflammatory activation state (enhanced phagocytotic and IFN-producing signature). Dicer-deficient GAMs showed reduced level of cyclin-dependent kinases (CDK1 and CDK2) and increased expression of CDK inhibitor p27 Kip1, thus manifesting impaired proliferation. Dicer knockout enhanced phagocytotic activity of GAMs to eliminate GL261 tumor cells. Increased proinflammatory GAM clusters in macrophage Dicer-deficient mice actively interacted with tumor-infiltrating T cells and NK cells through TNF paracrine signaling to create a pro-inflammatory immune microenvironment for tumor cell elimination. Our work identifies the role of Dicer deletion in macrophages in generating an immune-activating microenvironment, which could be further developed as a potential immunotherapeutic strategy against glioblastoma.

Efficacy of intravitreal conbercept injection on short- and long-term macular edema in branch retinal vein occlusion.

AIM: To observe the best-corrected visual acuity (BCVA) and central foveal thickness (CFT) repeatedly after the intravitreal injection of conbercept (IVC) for treating cystoid macular edema (CME) in branch retinal vein occlusion (BRVO) and explore the relationship between the duration of CME and visual outcome. METHODS: Subgroup analysis was performed to compare short-term (within 90d of CME onset) and long-term (over 90d of CME onset) macular edema in BRVO. After an initial IVC, a pro re nata (PRN) strategy was performed according to the recurrence of CFT or decrease of BCVA. Analysis of variance using repeated measurements, statistical analysis following indicators including BCVA and CFT collected at baseline and 1, 3, and 6mo after IVC. RESULTS: Among the 60 cases included in this retrospective study, 36 were short-term CME, and 24 were long-term CME. There were statistical significances between and within groups of the BCVAs at different time points (P<0.001). The interaction was found between group and time (P=0.006), indicating the difference in the speed of BCVA improvement between groups. In particular, the improvement speed of BCVA in the short-term CME group was faster than that in the long-term CME group. There were significant differences between and with groups of the CFT at different time points (P<0.001). However, the interaction between group and time in relation to CFT had no significant differences (P=0.59). CONCLUSION: IVC treatment for CME following BRVO is effective and safe. The duration of CME before treatment is a significant predictor of the visual outcomes of patients with BRVO. The improvement of vision might be faster with early IVC treatment than with delayed treatment.

HOXA5 is amplified in glioblastoma stem cells and promotes tumor progression by transcriptionally activating PTPRZ1.

Although the tumorigenic potential of glioma stem cells (GSCs) is associated with multiple molecular alterations, the gene amplification status of GSCs has not been elucidated. Overexpression of HomeoboxA5 (HOXA5) is associated with increased glioma malignancy. In this study, we identify the gene amplification and protein overexpression of HOXA5 in GSCs and its function in regulating GSC maintenance and the downstream transcriptional effector, to explore the significance of HOXA5 amplification/overexpression for GSC identification and prognostic determination. The HOXA5 gene is significantly amplified in glioblastoma (GBM) and is an independent prognostic factor for predicting worse patient outcomes. Specifically, HOXA5 gene amplification and the resultant protein overexpression are correlated with increased proportions of GSCs and enhanced self-renewal/invasiveness of these cells. Disruption of HOXA5 expression impairs GSC survival and GBM tumor propagation. Mechanistically, HOXA5 directly binds to the promoter region of protein tyrosine phosphatase receptor type Z1 (PTPRZ1), thereby upregulating this gene for GSC maintenance. Suppression of PTPRZ1 largely compromises the pro-tumoral effect of HOXA5 on GSCs. In summary, HOXA5 amplification serves as a genetic biomarker for predicting worse GBM outcome, by enhancing PTPRZ1-mediated GSC survival.

Overexpression of carnitine palmitoyltransferase 1A promotes mitochondrial fusion and differentiation of glioblastoma stem cells.

Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy.

Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling.

Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.

Within-visit and between-visit intra-individual blood pressure variability in an unselected adult population from rural China.

OBJECTIVE: To assess the association between the variability of blood pressure (BP) readings within an initial clinic visit, the variability within subsequent visits and the variability between visits over 1 week in a general population. METHODS: This study included 1401 adult residents, who were not taking antihypertensive drugs, having BP measurements at three visits over 1 week. The difference between maximal and minimal BP readings (ΔBP), ΔBP/BPm (the mean BP value in a visit), the standard deviation (SD) and coefficient of variation (coefficient of variation = SD × 100/mean) of three BP values in each visit were used to estimate the within-visit BP variability (BPV). The SD and coefficient of variation of all nine BP readings over the three visits were calculated as SD9 or CV9 to reflect the overall BPV during the study visits. The SD and coefficient of variation on the mean BP values (BPm) of three visits were computed as SD-3 or CV-3, whereas the difference between maximal and minimal BP in three visits was computed as ΔBP-3 to estimate visit-to-visit BPV. The average BP or HR was the mean values of nine BP or HR readings over three visits. RESULTS: The systolic and diastolic mean BP (SBP and DBP) decreased from the first to the third visit. The ΔBP, SD and coefficient of variation for both SBP and DBP at the first visit were positively and significantly correlated with the corresponding variables computed at the second and third visits, as well as with overall BPV (ΔBP9, SD9 and CV9). A positive correlation was also found between overall BPV and visit-to visit BPV (SD-3, CV-3 and ΔBP9). Multivariate analysis showed: no association between average SBP and systolic coefficient of variation or ΔBP/BPm but a negative association between average DBP and coefficient of variation or ΔBP/BPm for DBP at the first visit, DBP-3 and DBP9. Age was positively correlated with coefficient of variation or ΔBP/BPm for SBP at the first visit, SBP-3 and SBP9, and correlated with coefficient of variation and ΔBP/BPm for DBP only at the first visit. CONCLUSION: In a general population, within-visit BPV at an initial visit is associated with within-visit BPV at subsequent visits and with visit-to-visit BPV over three visits within 1 week.

Contrast-enhanced ultrasound using SonoVue mixed with oral gastrointestinal contrast agent to evaluate esophageal hiatal hernia: Report of three cases and a literature review.

BACKGROUND: Due to a thicker abdominal wall in some patients, ultrasound artifacts from gastrointestinal gas and surrounding tissues can interfere with routine ultrasound examination, precluding its ability to display or clearly show the structure of a hernial sac (HS) and thereby diminishing diagnostic performance for esophageal hiatal hernia (EHH). Contrast-enhanced ultrasound (CEUS) imaging using an oral agent mixture allows for clear and intuitive identification of an EHH sac and dynamic observation of esophageal reflux. CASE SUMMARY: In this case series, we report three patients with clinically-suspected EHH, including two females and one male with an average age of 67.3 ± 16.4 years. CEUS was administered with an oral agent mixture (microbubble-based SonoVue and gastrointestinal contrast agent) and identified a direct sign of supradiaphragmatic HS (containing the hyperechoic agent) and indirect signs [e.g., widening of esophageal hiatus, hyperechoic mixture agent continuously or intermittently reflux flowing back and forth from the stomach into the supradiaphragmatic HS, and esophagus-gastric echo ring (i.e., the "EG" ring) seen above the diaphragm]. All three cases received a definitive diagnosis of EHH by esophageal manometry and gastroscopy. Two lesions resolved upon drug treatment and one required surgery. The recurrence rate in follow-up was 0%. The data from these cases suggest that the new non-invasive examination method may greatly improve the diagnosis of EHH. CONCLUSION: CEUS with the oral agent mixture can facilitate clear and intuitive identification of HS and dynamic observation of esophageal reflux.