Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle‐derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24^?/? (Z24^?/?) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin‐induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F‐actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei‐induced cGAS‐Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24^?/? mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.     

Acarbose improved survival for Apc+/Min mice

Acarbose blocks the digestion of complex carbohydrates, and the NIA Intervention Testing Program (ITP) found that it improved survival when fed to mice. Yet, we do not know if lifespan extension was caused by its effect on metabolism with regard to the soma or cancer suppression. Cancer caused death for ~80% of ITP mice. The ITP found rapamycin, an inhibitor to the pro‐growth mTORC1 (mechanistic target of rapamycin complex 1) pathway, improved survival and it suppressed tumors in Apc^+/Min mice providing a plausible rationale to ask if acarbose had a similar effect. Apc^+/Min is a mouse model prone to intestinal polyposis and a mimic of familial adenomatous polyposis in people. Polyp‐associated anemia contributed to their death. To address this knowledge gap, we fed two doses of acarbose to Apc^+/Min mice. Acarbose improved median survival at both doses. A cross‐sectional analysis was performed next. At both doses, ACA fed mice exhibited reduced intestinal crypt depth, weight loss despite increased food consumption and reduced postprandial blood glucose and plasma insulin, indicative of improved insulin sensitivity. Dose‐independent and dose‐dependent compensatory liver responses were observed for AMPK and mTORC1 activities, respectively. Only mice fed the high dose diet exhibited reductions in tumor number with higher hematocrits. Because low‐dose acarbose improved lifespan but failed to reduced tumors, its effects seem to be independent of cancer. These data implicate the importance of improved carbohydrate metabolism on survival.     

Highly efficient soluble expression and purification of recombinant human basic fibroblast growth factor (hbFGF) by fusion with a new collagen-like protein (Scl2) in Escherichia coli

Abstract

Human basic fibroblast growth factor (hbFGF) is involved in a wide range of biological activities that affect the growth, differentiation, and migration. Due to its wound healing effects and therapy, hbFGF has the potential as therapeutic agent. Therefore, large-scale production of biologically active recombinant hbFGF with low cost is highly desirable. However, the complex structure of hbFGF hinders its high-level expression as the soluble and functional form. In the present study, an efficient, cost-effective, and scalable method for producing recombinant hbFGF was developed. The modified collagen-like protein (Scl2-M) from Streptococcus pyogenes was used as the fusion tag for producing recombinant hbFGF for the first time. After optimization, the expression level of Scl2-M-hbFGF reached approximately 0.85?g/L in the shake flask and 7.7?g/L in a high cell-density fermenter using glycerol as a carbon source. Then, the recombinant Scl2-M-hbFGF was readily purified using one-step acid precipitation and the purified Scl2-M-hbFGF was digested with enterokinase. The digested mixture was further subject to ion-exchange chromatography, and the final high-purity (96%) hbFGF product was prepared by freeze-drying. The recovery rate of the whole purification process attained 55.0%. In addition, the biological activity of recombinant hbFGF was confirmed by using L929 and BALB/c3T3 fibroblasts. Overall, this method has the potential for large scale production of recombinant hbFGF.     

Spatial distribution and environmental risk assessment of heavy metals identified in soil of a decommissioned uranium mining area

Abstract

The spatial distribution of six heavy metals (Cd, As, Zn, Pb, Cr, and Cu) in the soil of a decommissioned uranium mining area was investigated and their potential environmental risk was assessed. Soil samples were collected along the main riversides enclosing the mining area. The heavy metal distribution was determined by geospatial interpolation. Pearson correlation coefficient and principal component analysis were used to locate the sources of pollution which are the mine ore as natural source, and dressing plants and tailing area from human activity. The results indicate that the average concentrations of As and Cd strongly exceed the recommended EQSS (Environmental Quality Standard for Soils of China) limits at all sampling sites, whereas Zn concentrations were found to be slightly over the limit only at sampling sites close to the mining area. The concentrations of Cr, Cu and Pb were all within the recommended limits. Environmental risk was assessed using the toxicity characteristic leaching procedure defining the degree to which extend the metal is released into the solution. High leaching rates were found only for Zn and Cd, suggesting that together with its high concentrations Cd is the most toxic metal around the mining area, followed by As.     

Some Meaningful Weighted Log-Rank and Weighted Win Loss Statistics

Statistics in Biosciences - Weighted log-rank statistics and recently weighted win loss statistics are often used to test the null hypothesis that the treatment group and the control group have no...     

A rapid enantioseparation system of capillary electrochromatography modified by electrostatic adsorption with transfersomes

Transfersomes were a special kind of nanomaterials with higher deformability and flexibility. A rapid method for coated-column preparation using anionic transfersomes as a coating material by electrostatic adsorption was developed. With carboxymethyl-β-cyclodextrin added in running buffer as the chiral selector, the capillary electrochromatography enantioseparation system based on the transfersomes-coated column modified by electrostatic adsorption was established for the first time. Propranolol and metoprolol acted as model drugs to evaluate the enantioseparation performance, these two basic drugs achieved baseline separation with satisfactory resolution and selection factor in this transfersomes-electrochromatography system but only partial separation in bare column system. In order to get the optimal separation condition, concentration of chiral selector, buffer pH, and applied voltage were systematically investigated. A rapid and efficient enantioseparation electrochromatography system was established and showed that transfersomes as the stationary phase could efficiently improve chiral separation effect.     

An anti-inflammatory isoflavone from soybean inoculated with a marine fungus Aspergillus terreus C23-3

ABSTRACT

A new isoflavone derivative compound 1 (psoralenone) was isolated from soybean inoculated with a marine fungus Aspergillus terreus C23-3, together with seven known compounds including isoflavones 2–6, butyrolactone I (7) and blumenol A (8). Their structures were elucidated by MS, NMR, and ECD. Psoralenone displayed moderate in vitro anti-inflammatory activity in the LPS-induced RAW264.7 cell model. Compound 2 (genistein) showed moderate acetylcholinesterase (AChE) inhibitory activity whereas compounds 2, 5 (biochanin A), 6 (psoralenol), and 7 exhibited potent larvicidal activity against brine shrimp. Compounds 3 (daidzein), 4 (4?-hydroxy-6,7-dimethoxyisoflavone), and 5–7 showed broad-spectrum anti-microbial activity, and compound 7 also showed moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity.     

Evolution of putative barrier loci at an intermediate stage of speciation with gene flow in campions (Silene)

Understanding the origin of new species is a central goal in evolutionary biology. Diverging lineages often evolve highly heterogeneous patterns of genetic differentiation; however, the underlying mechanisms are not well understood. We investigated evolutionary processes governing genetic differentiation between the hybridizing campions Silene dioica (L.) Clairv. and S. latifolia Poiret. Demographic modelling indicated that the two species diverged with gene flow. The best‐supported scenario with heterogeneity in both migration rate and effective population size suggested that a small proportion of the loci evolved without gene flow. Differentiation (F _ST) and sequence divergence (d _XY) were correlated and both tended to peak in the middle of most linkage groups, consistent with reduced gene flow at highly differentiated loci. Highly differentiated loci further exhibited signatures of selection. In between‐species population pairs, isolation by distance was stronger for genomic regions with low between‐species differentiation than for highly differentiated regions that may contain barrier loci. Moreover, differentiation landscapes within and between species were only weakly correlated, suggesting that linked selection due to shared recombination and gene density landscapes is not the dominant determinant of genetic differentiation in these lineages. Instead, our results suggest that divergent selection shaped the genomic landscape of differentiation between the two Silene species, consistent with predictions for speciation in the face of gene flow.