Corticosterone Assimilation by a Voluntary Oral Administration in Palatable Food to Rats

Drug delivery in research on nonhuman animals in the laboratory is still challenging because it is usually invasive and stressful. Stress-free voluntary oral drug administration in water lacks precise control of dose and timing of substance ingestion. Voluntary oral consumption of corticosterone has been previously successfully applied in mice using oat flakes, but protocols for oral corticosterone administration in rats remain unavailable. This study assessed the effectiveness of voluntary oral administration to rats of a palatable piece of bread soaked with corticosterone that can be rapidly prepared and is reliably dose- and timing-controllable. After three familiarization days, all rats ate the bread within 120 seconds of presentation, irrespective of the presence or absence of corticosterone or vehicle. Corticosterone plasma levels remained at basal levels with consumption of vehicle-containing bread, and they were significantly increased with corticosterone-containing bread. Hence, the method enabled corticosterone bodily assimilation while avoiding stress, making it a possible alternative for invasive and stressful procedures. This article includes a methodological refinement that lessens unnecessary discomfort to laboratory animals and is potentially suitable for acute and chronic protocol studies.     

Evolution of Relapse-Proficient Subclones Constrained by Collateral Sensitivity to Oncogene Overdose in Wnt-Driven Mammary Cancer

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Length polymorphisms at two candidate genes explain variation of migratory behaviors in blackpoll warblers (Setophaga striata)

Migratory behaviors such as the timing and duration of migration are genetically inherited and can be under strong natural selection, yet we still know very little about the specific genes or molecular pathways that control these behaviors. Studies in candidate genes Clock and Adcyap1 have revealed that both of these loci can be significantly correlated with migratory behaviors in birds, though observed relationships appear to vary across species. We investigated geographic genetic structure of Clock and Adcyap1 in four populations of blackpoll warblers (Setophaga striata), a Neotropical–Nearctic migrant that exhibits geographic variation in migratory timing and duration across its boreal breeding distribution. Further, we used data on migratory timing and duration, obtained from light‐level geolocator trackers to investigate candidate genotype–phenotype relationships at the individual level. While we found no geographic structure in either candidate gene, we did find evidence that candidate gene lengths are correlated with five of the six migratory traits. Maximum Clock allele length was significantly and negatively associated with spring arrival date. Minimum Adcyap1 allele length was significantly and negatively associated with spring departure date and positively associated with fall arrival date at the wintering grounds. Additionally, we found a significant interaction between Clock and Adcyap1 allele lengths on both spring and fall migratory duration. Adcyap1 heterozygotes also had significantly shorter migration duration in both spring and fall compared to homozygotes. Our results support the growing body of evidence that Clock and Adcyap1 allele lengths are correlated with migratory behaviors in birds.     

基于CiteSpace分析铜绿假单胞菌耐药性研究热点与趋势

【背景】铜绿假单胞菌(Pseudomonas aeruginosa)是临床引发感染的主要病原菌之一,对多种抗菌药物均有耐药性,临床治疗难度大,对该病原菌耐药性的研究一直备受关注。【目的】基于CiteSpace可视化功能,探究铜绿假单胞菌耐药性研究现状、热点与发展趋势。【方法】利用文献计量分析法,以2014–2021年中国知网(CNKI)、万方数据库(Wanfang)、Web of Science (WoS)共8 996篇铜绿假单胞菌耐药性的中英文文献为分析样本,运用Citespace软件对文献发文量、作者合作网络、国家和机构合作网络、文献共被引及期刊分析、关键词聚类、突现等方面进行分析,以探究该研究主题的研究热点及趋势。【结果】英文文献发文量增长速度高于中文文献;我国文献发文量仅次于美国、印度,在该领域科研成果贡献度较高,国际学术影响力较大;中英文文献中均对院内感染疾病和耐碳青霉烯类铜绿假单胞菌持高关注度。然而,中文文献较关注铜绿假单胞菌耐药性的临床防治问题,英文文献则较关注铜绿假单胞菌耐药性的基础研究。【结论】国内外铜绿假单胞菌耐药性研究对院内感染疾病及新型耐药菌的产生与防治关注度最高,暗示以上研究主题是该领域的研究热点与趋势。     

强化玉米饮食对小鼠肠道菌群结构和功能的影响

【目的】采用高通量测序方法研究强化玉米饮食对小鼠肠道菌群结构的影响以及可提高宿主糖代谢相关菌群功能基因的分析。【方法】分别给予两组小鼠(各10只)常规饮食和强化玉米饮食(1/4的玉米粉加3/4的常规饮食成分),喂养10周,之后采集小鼠粪便样本,提取DNA,使用高通量测序仪进行宏基因组测序分析,比较两组小鼠肠道菌群和功能基因的差异。【结果】两组小鼠的终末体重没有明显差异。各样本DNA的测序有效率足够,肠道菌群的多样性存在一定差异。属放线菌门(Actinobacteria)的双歧杆菌(Bifidobacteriales)-B.pseudolongum分支和Coriobacteriia-Collinsella/Enterorhabdus分支的丰度在强化玉米饮食组的小鼠中显著升高,相应的宏基因组中涉及糖酵解和胆汁酸合成的一些酶和功能单元的含量也在强化玉米饮食组显著升高。【结论】强化玉米饮食可以提高肠道菌群中双歧杆菌等益生菌的丰度,增加宏基因组糖脂代谢相关基因和通路的含量,从而可能促进宿主的糖代谢功能。     

Local FK506 dose-dependent study using a novel three-dimensional organotypic assay

Local administration of FK506, an FDA approved immunosuppressant with neuroregenerative properties, is a promising technique to achieve improved peripheral nerve regeneration while preventing the side effects associated with the systemic administration of this drug. Although considerable research has been devoted to the development of clinically suitable systems for local delivery of FK506 to the site of nerve injury and repair, the optimal dose of FK506 for enhancement of axon regeneration in the peripheral nerve has not yet been established. To this end, we devised a three-dimensional (3D) organotypic assay capable of mimicking the peripheral nerve. This assay consisted of a neonatal rat dorsal root ganglion (DRG) extending its neurites into the native peripheral nerve scaffold provided by an acellular nerve allograft (ANA). A novel 3D compartmented cell culture system was adapted from the 3D organotypic assay to achieve local delivery of FK506 just to the growing neurites in vitro and establish the required local dose of FK506 for peripheral nerve regeneration. A bimodal dose response was observed by culturing the entire DRG–ANA construct with media containing different concentrations of FK506. Low drug concentration of 1 pg/ml and high drug concentration of 100 ng/ml lead to the longest neurite extension in vitro. Furthermore, regardless of the FK506 concentration, concentrating the drug to the growing neurites resulted in significant increase in both neurite extension and neurite density, an effect that was not observed with the FK506 delivery to both neurites and neural cell bodies within DRG. The findings in this study provide valuable insight into the optimal local dose of FK506 for peripheral nerve regeneration. Furthermore, for the first time, this study suggests the potential interaction of FK506 with axons at the level of the growth cone.     

Drug-delivering nerve conduit improves regeneration in a critical-sized gap

Autologous nerve grafts are the current “gold standard” for repairing large nerve gaps. However, they cause morbidity at the donor nerve site and only a limited amount of nerve can be harvested. Nerve conduits are a promising alternative to autografts and can act as guidance cues for the regenerating axons, without the need to harvest donor nerve. Separately, it has been shown that localized delivery of GDNF can enhance axon growth and motor recovery. FK506, an FDA approved small molecule, has also been shown to enhance peripheral nerve regeneration. This paper describes the design of a novel hole-based drug delivery apparatus integrated with a polytetrafluoroethylene (PTFE) nerve conduit for controlled local delivery of a protein such as GDNF or a small molecule such as FK506. The PTFE devices were tested in a diffusion chamber, and the bioactivity of the released media was evaluated by measuring neurite growth of dorsal root ganglions (DRGs) exposed to the released drugs. The drug delivering nerve guide was able to release bioactive concentrations of FK506 or GDNF. Following these tests, optimized drug releasing nerve conduits were implanted across 10 mm sciatic nerve gaps in a BL6 yellow fluorescent protein (YFP) mouse model, where they demonstrated significant improvement in muscle mass, compound muscle action potential, and axon myelination in vivo as compared with nerve conduits without the drug. The drug delivery nerve guide could release drug for extended periods of time and enhance axon growth in vitro and in vivo.     

Alginate as a support ligand for enhanced colloidal liquid aphron immobilization of proteins and drug delivery

Research within the field of colloidal liquid aphrons (CLAs) for enzyme immobilization has often used ionic surfactants for the retention of enzymes. Although these charged interactions allow for enhanced immobilization, they can often lead to denaturation of enzyme activity, and even release of the protein. Sodium alginate has been used in drug delivery applications due to its low toxicity and charged interactions that allow for encapsulation. Hence, alginate systems can be used as an alternative to ionic surfactants in CLA immobilization. This paper presents, for the first time, the use of sodium alginate as potential ligand for enhanced CLA immobilization. The use of five model proteins; lysozyme, bovine serum albumin, ovalbumin, insulin, and α-chymotrypsin, of various pIs and hydrophobicities, showed the relevance of electrostatic interactions in promoting binding with sodium alginate when the pH < pI, with 100% immobilization attributed to alginate incorporated CLAs over general nonionic formulations. Furthermore, above their pI, >80% protein recovery was observed, with activity and conformation comparable to their native counterparts. Finally, the use of proteolysis showed that as the degree of ionic bonding increased between the protein and sodium alginate, the degree of protease resistance decreased due to conformational changes experienced during binding.     

抗衰老药物对线虫生存曲线影响的荟萃分析

随着世界人口老龄化步伐的加快,衰老机制及抗衰老药物的研究日益成为生物医学领域的热点前沿之一.国内外已有大量研究报道抗衰老药物能够延长多种模式生物包括线虫、果蝇、小鼠、大鼠及灵长类等的寿命,然而,这些药物延缓衰老方式的差异仍缺乏系统研究.因此,本研究以衰老研究的热点模式生物线虫为对象,搜集1990年以来国内外刊物上正式发表的有关抗衰老药物寿命试验的研究文献及其涉及的生存曲线,利用荟萃分析比较了不同抗衰老药物与生存曲线变化类型间的关系,并结合药物的药理作用探讨其延寿机制.生存曲线特征聚类结果与药物生物学分类交叉分析结果表明,药理作用类型与增益类型具有很强相关性,提示这2种分类方法的结果是匹配的.抗氧化剂类药物和控制血糖类药物对生存曲线的改善总体增益虽然不是最高,但相对于正常组生存曲线其增益部分呈平移形,表明该类药物可以通过改善年龄结构对整个群体产生显著增益,且其衰老曲线的特征与自然衰老相似.抗癫痫药物及胃肠道菌群相关药物总体增益较大,其曲线增益形状呈梯形,提示该类药物(尤其是胃肠道菌群相关药物)尽管显著延长了少数个体的最大寿命,但是从整个群体来看,大多数个体寿命延长程度并不明显,受益的少数个体可能需要较长的外界资源支持方能保持较长时间的存活状态,这种模式既不大众化也不经济.综上所述,清除自由基和控制血糖类药物对健康老年有着更为积极合理的作用与效应.