Phase I randomised clinical trial of an HIV-1(CN54), clade C, trimeric envelope vaccine candidate delivered vaginally

We conducted a phase 1 double-blind randomised controlled trial (RCT) of a HIV-1 envelope protein (CN54 gp140) candidate vaccine delivered vaginally to assess immunogenicity and safety. It was hypothesised that repeated delivery of gp140 may facilitate antigen uptake and presentation at this mucosal surface. Twenty two healthy female volunteers aged 18-45 years were entered into the trial, the first receiving open-label active product. Subsequently, 16 women were randomised to receive 9 doses of 100 μg of gp140 in 3 ml of a Carbopol 974P based gel, 5 were randomised to placebo solution in the same gel, delivered vaginally via an applicator. Participants delivered the vaccine three times a week over three weeks during one menstrual cycle, and were followed up for two further months. There were no serious adverse events, and the vaccine was well tolerated. No sustained systemic or local IgG, IgA, or T cell responses to the gp140 were detected following vaginal immunisations. Repeated vaginal immunisation with a HIV-1 envelope protein alone formulated in Carbopol gel was safe, but did not induce local or systemic immune responses in healthy women. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637962.     

Interplay between Sumoylation and Phosphorylation for Protection against α-Synuclein Inclusions

Parkinson disease is associated with the progressive loss of dopaminergic neurons from the substantia nigra. The pathological hallmark of the disease is the accumulation of intracytoplasmic inclusions known as Lewy bodies that consist mainly of post-translationally modified forms of α-synuclein. Whereas phosphorylation is one of the major modifications of α-synuclein in Lewy bodies, sumoylation has recently been described. The interplay between α-synuclein phosphorylation and sumoylation is poorly understood. Here, we examined the interplay between these modifications as well as their impact on cell growth and inclusion formation in yeast. We found that α-synuclein is sumoylated in vivo at the same sites in yeast as in human cells. Impaired sumoylation resulted in reduced yeast growth combined with an increased number of cells with inclusions, suggesting that this modification plays a protective role. In addition, inhibition of sumoylation prevented autophagy-mediated aggregate clearance. A defect in α-synuclein sumoylation could be suppressed by serine 129 phosphorylation by the human G protein-coupled receptor kinase 5 (GRK5) in yeast. Phosphorylation reduced foci formation, alleviated yeast growth inhibition, and partially rescued autophagic α-synuclein degradation along with the promotion of proteasomal degradation, resulting in aggregate clearance in the absence of a small ubiquitin-like modifier. These findings suggest a complex interplay between sumoylation and phosphorylation in α-synuclein aggregate clearance, which may open new horizons for the development of therapeutic strategies for Parkinson disease.     

Sensitivity of random amplified polymorphic DNA analysis to detect genetic change in sugarcane during tissue culture

Random amplified polymorphic DNA (RAPD) analysis using 10-mer oligonucleotide primers efficiently differentiated sugarcane cultivars and proved suitable for detecting gross genetic change such as that which can occur in sugarcane subjected to prolonged tissue culture, for example in protoplast-derived callus. However, RAPD analysis was not sufficiently sensitive to detect smaller genetic changes that occur during sugarcane genetic transformation. The length of DNA scored for polymorphism per primer averaged 13.2 kb, or 0.0001% of the typical sugarcane genome size of 1.2 × 10₇ kb (2C). RAPD analysis of sugarcane plants regenerated from embryogenic callus revealed very few polymorphisms, indicating that gross genetic change is infrequent during this tissue culture procedure, although epigenetic effects result in transient morphological changes in regenerated plants. More sensitive variations on the RAPD technique may increase the practicality of DNA-based screening of regenerated plant lines to reveal somaclonal variants.     

Effect of straw on the behaviour of growing pigs

The effects of straw on the behaviour of young growing pigs were studied in two experiments. In Experiment 1, groups of three pigs, aged about 7 weeks, were housed in raised decks with or without straw bedding. Time-lapse video recording showed no major differences between treatments in the amount or daily pattern of overall activity and feeding. Detailed observations showed that bedding reduced the incidence of rooting and chewing on pen-mates, but had little effect on other social activities such as mounting and aggressive biting. Experiment 2 compared groups of eight growing pigs aged about 10 weeks, housed in floor pens with or without a small amount of straw provided daily in a rack. Pigs with straw concentrated more of their daily activity into the period when straw was fresh, but the total amount of overall activity and time spent feeding were not affected. Rooting and chewing of pen-mates were the only social activities reduced by the provision of fresh straw. In these studies, where straw was not required to compensate for deficiencies such as low temperatures or hunger, the one major function of straw was to provide a stimulus and outlet for rooting and chewing, with a resulting reduction in such activities directed at pen-mates.     

裕固族血脂异常人群肠道菌群结构特征分析

探究生活在相同环境下的同一民族血脂异常人群与健康人群的肠道菌群差异,为血脂异常的精准预防和治疗提供参考。

收集甘肃肃南县裕固族血脂异常人群和健康人群粪便样本,提取细菌总DNA,通过16S rDNA高通量测序和生物信息学技术,分析2组人群肠道菌群的差异。

裕固族健康组人群肠道菌群分属26个门,73个纲,169个目,301个科,709个属,门水平上丰度＞1%的物种有4个,属水平上丰度＞1%的物种有22个。裕固族血脂异常组人群肠道菌群分属29个门,75个纲,280个目,304个科,702个属,门水平上丰度＞1%的物种有4个,属水平上丰度＞1%的物种有15个。裕固族血脂异常组人群肠道菌群与健康组间拟杆菌门、厚壁菌门、放线菌门水平以及F/B比值存在显著差异,Р＜0.05的差异物种有5个,Subdoligranulum、Christensenellaceae_R-7_group及Dialister与血脂水平呈负相关,Lachnoclostridium、Parasutterella与血脂水平呈正相关。

肃南县裕固族血脂异常组人群肠道菌群结构与健康组存在差异,为下一步关联分析肠道菌群与血脂异常及环境因素提供了基础数据。

     

Effects of water discharge on fledging time,growth, and survival of piping plovers on the Missouri River

River flow management and modification is a global issue, and its effects on river-dependent organisms are pervasive. Flow modification can directly affect avian species through mortality or habitat loss, but less is known about indirect and sublethal effects of flow modification on reproductive output in these species. Young birds are more vulnerable to predation between hatching and fledging than after flight is achieved, but tradeoffs must be made to balance growth and survival. Predation pressure appears to be a significant factor affecting the time to fledging in altricial birds, but less is known about this threat for precocial birds. Birds reaching fledging earlier should have greater rates of survival to migration because their predator escape repertoire includes flight at an earlier age. We evaluated the effect of varying outflows from the Gavins Point Dam on the growth, age at fledging, and survival of piping plover (Charadrius melodus) chicks on the Missouri River (2006–2009). The study was characterized by 2 relatively high flow years (2006 and 2009) and 2 relatively low flow years (2007 and 2008). We used success rate in recapturing chicks in capture–mark–recapture models as an index for fledging. We attempted to recapture all chicks (n = 1,099) by hand every 3–4 days throughout the season to acquire morphological measurements. Models indicated that as flows from the dam increased, age at fledging increased. We also found that increasing flows were associated with decreasing daily survival rates (β_flow = −2.401, 95% CI: −4.351 to −0.452). Flow was also negatively related to chick mass gain, but we found less evidence for an effect on wing-chord length. Increased flows covered wet-substrate foraging habitat, and likely affected plover reproductive output directly through chick survival and indirectly through decreased growth and increased fledging times. © The Wildlife Society, 2013     

Structural Variation and Uniformity among Tetraloop-Receptor Interactions and Other Loop-Helix Interactions in RNA Crystal Structures

Tetraloop-receptor interactions are prevalent structural units in RNAs, and include the GAAA/11-nt and GNRA-minor groove interactions. In this study, we have compiled a set of 78 nonredundant loop-helix interactions from X-ray crystal structures, and examined them for the extent of their sequence and structural variation. Of the 78 interactions in the set, only four were classical GAAA/11-nt motifs, while over half (48) were GNRA-minor groove interactions. The GNRA-minor groove interactions were not a homogeneous set, but were divided into five subclasses. The most predominant subclass is characterized by two triple base pair interactions in the minor groove, flanked by two ribose zipper contacts. This geometry may be considered the “standard” GNRA-minor groove interaction, while the other four subclasses are alternative ways to form interfaces between a minor groove and tetraloop. The remaining 26 structures in the set of 78 have loops interacting with mostly idiosyncratic receptors. Among the entire set, a number of sequence-structure correlations can be identified, which may be used as initial hypotheses in predicting three-dimensional structures from primary sequences. Conversely, other sequence patterns are not predictive; for example, GAAA loop sequences and GG/CC receptors bind to each other with three distinct geometries. Finally, we observe an example of structural evolution in group II introns, in which loop-receptor motifs are substituted for each other while maintaining the larger three-dimensional geometry. Overall, the study gives a more complete view of RNA loop-helix interactions that exist in nature.