Bone tissue has an exceptional quality to regenerate to native tissue in response to injury. However, the fracture repair process requires mechanical stability or a viable biological microenvironment or both to ensure successful healing to native tissue. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. Preclinical and clinical studies using biologic agents like recombinant bone morphogenetic proteins have demonstrated an efficacy similar or better than that of autologous bone graft in acute fracture healing. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications. 相似文献
Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies. 相似文献
The literature offers no consensus as to whether the delta(13)C of respired CO(2) is identical to that of the respiratory substrate, perhaps because of differences in measurement technique and growth conditions. To address this issue, the delta(13)C of respired CO(2) from growing sunflower shoot apices was measured and compared with that of soluble carbohydrates extracted from the respiring tissues. Shoot apices were studied because any influence of growth and biosynthesis was expected to be maximally expressed in these rapidly growing tissues. The two most probable substrates, starch and soluble sugars, were similar in delta(13)C (P=0.46). The delta(13)C of respired CO(2) was enriched in (13)C compared with these putative substrates (P<0.0001). This apparent enrichment ranged from 2.2 per thousand-5.7 per thousand, and decreased with relative growth rate (P<0.0001). The respiratory enrichment was counterbalanced by a depletion in the tissue constructed from the residual carbohydrates. The depletion varied from 2.2 per thousand to 3.0 per thousand relative to soluble carbohydrates (P<0.05), as predicted from mass-balance arguments. These results support the idea that respired CO(2) is enriched relative to its substrates. Variation in growth rates may help to explain the variable amounts of respiratory discrimination described in the literature. 相似文献
Plant and Soil - Water is the primary limiting factor for plants in drylands, which are projected to become even drier with climate change. Plant functional traits related to water influences... 相似文献
The alga polytomella contains several organelles composed of microtubules, including four flagella and hundreds of cytoskeletal microtubules. Brown and co-workers have shown (1976. J. Cell Biol. 69:6-125; 1978, Exp. Cell Res. 117: 313-324) that the flagella could be removed and the cytoskeletans dissociated, and that both structures could partially regenerate in the absence of protein synthesis. Because of this, and because both the flagella and the cytoskeletons can be isolated intact, this organism is particularly suitable for studying tubulin heterogeneity and the incorporation of specific tubulins into different microtubule-containing organelles in the same cell. In order to define the different species of tubulin in polytonella cytoplasm, a (35)S- labeled cytoplasmic fraction was subjected to two cycles of assembly and disassembly in the presence of unlabeled brain tubulin. Comparison of the labeled polytomella cytoplasmic tubulin obtained by this procedure with the tubulin of isolated polytomella flagella by two-dimensional gel electrophoresis showed that, whereas the β-tubulin from both cytoplasmic and flagellar tubulin samples comigrated, the two α-tubulins had distinctly different isoelectic points. As a second method of isolating tubulin from the cytoplasm, cells were gently lysed with detergent and intact cytoskeletons obtained. When these cytoskeletons were exposed to cold temperature, the proteins that were released were found to be highly enriched in tubulin; this tubulin, by itself, could be assembled into microtubules in vitro. The predominant α-tubulin of this in vitro- assembled cytoskeletal tubulin corresponded to the major cytoplasmic α-tubulin obtained by coassembly of labeled polytomella cytoplasmic extract with brain tubulin and was quite distinct from the α-tubulin of purified flagella. These results clearly show that two different microtubule-containing organelles from the same cell are composed of distinct tubulins. 相似文献
A genomic library of partially EcoRI-digested DNA from the lesser snow
goose, Anser caerulescens caerulescens, was constructed in the phage vector
Charon 4. Phage containing only unique sequences were identified by
screening plaques with 32P-labeled genomic DNA. Restriction-fragment-
length polymorphisms (RFLPs) were identified by probing DNA from 11-13 male
birds from the breeding colony at La Perouse Bay. Of the 17 probes
examined, all detected RFLPs with at least one of EcoRi, HindIII, Msp1, and
Taq1. Several of them identified highly variable regions with multiple
alleles. These RFLPs are valuable DNA markers that can be used for (1) the
examination of DNA variation, relatedness, and genetic distance and (2)
assessing paternity and maternity. These data suggest that there are higher
levels of variation of DNA sequence in birds than had previously been
thought to exist.
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ADP-glucose pyrophosphorylase (AGP) represents a key regulatory step in polysaccharide synthesis in organisms ranging from bacteria to plants. Higher plant AGPs are complex in nature and are heterotetramers consisting of two similar but distinct subunits. How the subunits are assembled into enzymatically active polymers is not yet understood. Here, we address this issue by using naturally occurring null mutants of the Shrunken2 (Sh2) and Brittle2 (Bt2) loci of maize as well as the yeast two-hybrid expression system. In the absence of the maize endosperm large AGP subunit (SH2), the BT2 subunit remains as a monomer in the developing endosperm. In contrast, the SH2 protein, in the absence of BT2, is found in a complex of 100 kD. A direct interaction between SH2 and BT2 was proven when they were both expressed in yeast. Several motifs are essential for SH2:BT2 interaction because truncations removing the N or C terminus of either subunit eliminate SH2:BT2 interactions. Analysis of subunit interaction mutants (sim) also identified motifs essential for protein interactions. 相似文献
Wet meadows are a common focus of wetland restoration efforts, and the species within them often exist within a restricted range of water levels. Unfortunately, many restored wetlands have higher water levels and more open water than naturally occurring reference wetlands, and many are invaded and dominated by species of Typha. Most studies evaluating the optimal water level for plant species use observational methods, yet experimental methods are required to understand the breadth of a species’ niche. We used experimental transplants of Carex pellita, a common wet meadow sedge used in restoration in the interior of the USA, and Typha latifolia, a species of cattail which invades many restored wetlands, to test whether higher water levels in a restored wetland were prohibitive to the target sedge species. Physiological and growth measurements were collected on both species. We found that C. pellita grew as well or better when transplanted into the ponded water levels, while T. latifolia had reduced growth when transplanted into the relatively drier meadow conditions. Interestingly, C. pellita was able to adjust its Turgor Loss Point in response to changing water levels. Only recently the assumption of a constant Turgor Loss Point for each species has been questioned. Our results provide evidence that wet meadow species have a broader hydrologic niche than previously thought, and their ability to make physiological adjustments in response to changing water levels may allow them to thrive in areas with widely varying water levels.