Heterotopic ossification (HO) refers to the pathological formation of ectopic bone in soft tissues, it occurs following severe trauma or in patients with a rare genetic disorder known as fibrodysplasia ossificans progressiva. The pathological process of HO formation is a two-step mechanism: inflammation and destruction of connective tissues, followed by bone formation. The latter is further subdivided into three stages: fibroproliferation/angiogenesis, chondrogenesis, and osteogenesis. Currently, therapeutic options for HO are limited. New potential therapeutics will most likely arise from a more detailed understanding of the signaling pathways implicated in each stage of ectopic bone formation and molecular targets that may be effective at both the early and late stages of HO. Bone morphogenetic protein (BMP) signaling is believed to play a key role in the overall HO process. Recently, the mammalian target of rapamycin (mTOR) signaling pathway has received attention as a critical pathway for chondrogenesis, osteogenesis, and HO. Inhibition of mTOR signaling has been shown to block trauma-induced and genetic HO. Intriguingly, recent studies have revealed crosstalk between mTOR and BMP signaling. Moreover, mTOR has emerged as a factor involved in the early hypoxic and inflammatory stages of HO. We will summarize the current knowledge of the roles of mTOR and BMP signaling in HO, with a particular focus on the crosstalk between mTOR and BMP signaling. We also discuss the activation of AMP activated protein kinase (AMPK) by the most widely used drug for type 2 diabetes, metformin, which exerts a dual negative regulatory effect on mTOR and BMP signaling, suggesting that metformin is a promising drug treatment for HO. The discovery of an mTOR-BMP signaling network may be a potential molecular mechanism of HO and may represent a novel therapeutic target for the pharmacological control of HO. 相似文献
Molecular Biology Reports - Peanut (Arachis hypogaea L.) is an important food and oilseed crop worldwide. Yield and quality can be significantly reduced by foliar fungal diseases, such as early and... 相似文献
The Arabian Sea is a heterogeneous region with high coral cover and warm stable conditions at the western end (Djibouti), in contrast to sparse coral cover, cooler temperatures, and upwelling at the eastern end (southern Oman). We tested for barriers to dispersal across this region (including the Gulf of Aden and Gulf of Oman), using mitochondrial DNA surveys of 11 reef fishes. Study species included seven taxa from six families with broad distributions across the Indo-Pacific and four species restricted to the Arabian Sea (and adjacent areas). Nine species showed no significant genetic partitions, indicating connectivity among contrasting environments spread across 2000 km. One butterflyfish (Chaetodon melannotus) and a snapper (Lutjanus kasmira) showed phylogenetic divergences of d = 0.008 and 0.048, respectively, possibly indicating cryptic species within these broadly distributed taxa. These genetic partitions at the western periphery of the Indo-Pacific reflect similar partitions recently discovered at the eastern periphery of the Indo-Pacific (the Hawaiian and the Marquesan Archipelagos), indicating that these disjunctive habitats at the ends of the range may serve as evolutionary incubators for coral reef organisms.
Most Ty1 retrotransposons in the genome of Saccharomyces cerevisiae are transpositionally competent but rarely transpose. We screened yeast mutagenized by insertion of the mTn3-lacZ/LEU2 transposon for mutations that result in elevated Ty1 cDNA-mediated mobility, which occurs by cDNA integration or recombination. Here, we describe the characterization of mTn3 insertions in 21 RTT (regulation of Ty1 transposition) genes that result in 5- to 111-fold increases in Ty1 mobility. These 21 RTT genes are EST2, RRM3, NUT2, RAD57, RRD2, RAD50, SGS1, TEL1, SAE2, MED1, MRE11, SCH9, KAP122, and 8 previously uncharacterized genes. Disruption of RTT genes did not significantly increase Ty1 RNA levels but did enhance Ty1 cDNA levels, suggesting that most RTT gene products act at a step after mRNA accumulation but before cDNA integration. The rtt mutations had widely varying effects on integration of Ty1 at preferred target sites. Mutations in RTT101 and NUT2 dramatically stimulated Ty1 integration upstream of tRNA genes. In contrast, a mutation in RRM3 increased Ty1 mobility >100-fold without increasing integration upstream of tRNA genes. The regulation of Ty1 transposition by components of fundamental pathways required for genome maintenance suggests that Ty1 and yeast have coevolved to link transpositional dormancy to the integrity of the genome. 相似文献
A new multimodal confocal microscope has been developed, which includes a parallel Partial Wave Spectroscopic (PWS) microscopy path. This combination of modalities allows molecular‐specific sensing of nanoscale intracellular structure using fluorescent labels. Combining molecular specificity and sensitivity to nanoscale structure allows localization of nanostructural intracellular changes, which is critical for understanding the mechanisms of diseases such as cancer. To demonstrate the capabilities of this multimodal instrument, we imaged HeLa cells treated with valinomycin, a potassium ionophore that uncouples oxidative phosphorylation. Colocalization of fluorescence images of the nuclei (Hoechst 33342) and mitochondria (anti‐mitochondria conjugated to Alexa Fluor 488) with PWS measurements allowed us to detect a significant decrease in nuclear nanoscale heterogeneity (Σ), while no significant change in Σ was observed at mitochondrial sites. In addition, application of the new multimodal imaging approach was demonstrated on human buccal samples prepared using a cancer screening protocol. These images demonstrate that nanoscale intracellular structure can be studied in healthy and diseased cells at molecular‐specific sites.
The segregational stability of a small, theta-replicating, non-mobilizable shuttle plasmid (pAEX-5E) was determined in fully virulent (pX01+/pX02+), partially cured (pX01+/pX02- and pX01-/pX02+) and fully cured (pX01-/pX02-) derivatives of Bacillus anthracis var. New Hampshire. Under the growth conditions used (L-broth, 37 degrees C, aerobic, batch culture), pAEX-5E remained segregationally stable in the pX01-/pX02+ and pX01-/pX02- derivatives for in excess of 100 culture generations, but was expelled from the pX01+/pX02+ and pX01+/pX02- derivatives (100% loss occurred after 101+/-3.8 and 54+/-6.0 culture generations, respectively). In the presence of antibiotic selection pressure to maintain pAEX-5E (5 microg erythromycin ml-1) no comparable loss of pX01 or pX02 was observed over 100 generations of growth in any of the derivatives of B. anthracis. Under these conditions the pX01+/pX02- derivative had an extended culture doubling time (td+/-S. E. of the mean) of 75.3 +/- 1.4 min compared with 47.3 +/- 1.1, 46.2 +/- 0.86 and 43.2 +/- 1.2 min for the pX01+/pX02+, pX01-/pX02+ and pX01-/pX02- derivatives, respectively. That antibiotic resistance was pAEX-5E-mediated was confirmed using a second antibiotic marker (kanamycin). After100 generations of growth in the presence of erythromycin, colonies were shown to have retained kanamycin resistance. Southern blot analysis, in conjunction with plasmid rescue to Escherichia coli confirmed that, after 100 culture generations in the presence of antibiotic selection pressure, pAEX-5E had remained structurally stable and had not integrated into the B. anthracis genome. 相似文献
Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the “class 3” epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies. 相似文献