Evaluation of putative CSF biomarkers in paediatric spinal muscular atrophy (SMA) patients before and during treatment with nusinersen

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disorder leading to immobilization and premature death. Currently, three alternative therapeutic options are available. Therefore, biomarkers that might reflect or predict the clinical course of the individual patient with treatment are of great potential use. Currently, the antisense oligonucleotide nusinersen is the prevalent and longest validated therapy for SMA. We analysed CSF candidate biomarkers for degenerative CNS processes (namely phosphorylated heavy chain (pNf-H), light-chain neurofilaments (NfL), total tau protein (T-Tau), neurogranin, β-secretase BACE-1 and alpha-synuclein) in 193 CSF samples of 44 paediatric SMA types 1, 2 and 3 patients before and under nusinersen treatment and related them to standardized clinical outcome scores in a single-centre pilot study. pNf-H and NfL correlated with disease severity and activity, emphasizing their relevance as marker of neuronal loss and clinical outcome. T-Tau was significantly correlated with motor function scores in SMA type 1 making it an interesting marker for treatment response. Additionally, baseline T-Tau levels were elevated in most SMA patients possibly reflecting the extension of neuronal degeneration in paediatric-onset SMA. Further investigations of these CSF proteins might be beneficial for paediatric SMA subtypes and treatment modalities as an indicator for clinical outcome and should be analysed in larger cohorts.     

Aerobic granular sludge: recent advances

Aerobic granulation, a novel environmental biotechnological process, was increasingly drawing interest of researchers engaging in work in the area of biological wastewater treatment. Developed about one decade ago, it was exciting research work that explored beyond the limits of aerobic wastewater treatment such as treatment of high strength organic wastewaters, bioremediation of toxic aromatic pollutants including phenol, toluene, pyridine and textile dyes, removal of nitrogen, phosphate, sulphate and nuclear waste and adsorption of heavy metals. Despite this intensive research the mechanisms responsible for aerobic granulation and the strategy to expedite the formation of granular sludge, and effects of different operational and environmental factors have not yet been clearly described. This paper provides an up-to-date review on recent research development in aerobic biogranulation technology and applications in treating toxic industrial and municipal wastewaters. Factors affecting granulation, granule characterization, granulation hypotheses, effects of different operational parameters on aerobic granulation, response of aerobic granules to different environmental conditions, their applications in bioremediations, and possible future trends were delineated. The review attempts to shed light on the fundamental understanding in aerobic granulation by newly employed confocal laser scanning microscopic techniques and microscopic observations of granules.     

An evaluation of condition indices and predictive models for noninvasive estimates of lipid mass of migrating Common Yellowthroats, Ovenbirds, and Swainson's Thrushes

ABSTRACT.   Noninvasive methods of measuring lipid mass in birds are widely used, but not frequently evaluated. I evaluated the ability of three noninvasive indicators of fat content (fat scores, body mass, body mass/wing chord) and regression models to predict lipid mass in two migratory songbirds previously unexamined in this context—Common Yellowthroat ( Geothlypis trichas ) and Ovenbird ( Seiurus aurocapillus ). I also examined the accuracy of these methods for Swainson's Thrushes ( Catharus ustulatus ) for comparison to a previous study. Fat score, body mass, and body mass/wing chord were highly correlated with chemically extracted lipid mass in each species. In all three species, birds with no visible subcutaneous fat possessed considerable quantities of fat, ranging from 9.8 to 19.7% of total dry body mass. Forward-selected regression models explained 69−87% of lipid mass variation, with prediction errors of 14.6−27.5%. An existing predictive model for the Swainson's Thrush overestimated lipid mass by an average of 92%. Fat score, body mass, and the regression models generated here are reliable predictors of lipid mass in two of the three migrating species examined. The accuracy of the methods, in addition to their low cost and simplicity, justifies their continued use in field studies of birds.     

A distance-dependent atomic knowledge-based potential for improved protein structure selection.

A heavy atom distance-dependent knowledge-based pairwise potential has been developed. This statistical potential is first evaluated and optimized with the native structure z-scores from gapless threading. The potential is then used to recognize the native and near-native structures from both published decoy test sets, as well as decoys obtained from our group's protein structure prediction program. In the gapless threading test, there is an average z-score improvement of 4 units in the optimized atomic potential over the residue-based quasichemical potential. Examination of the z-scores for individual pairwise distance shells indicates that the specificity for the native protein structure is greatest at pairwise distances of 3.5-6.5 A, i.e., in the first solvation shell. On applying the current atomic potential to test sets obtained from the web, composed of native protein and decoy structures, the current generation of the potential performs better than residue-based potentials as well as the other published atomic potentials in the task of selecting native and near-native structures. This newly developed potential is also applied to structures of varying quality generated by our group's protein structure prediction program. The current atomic potential tends to pick lower RMSD structures than do residue-based contact potentials. In particular, this atomic pairwise interaction potential has better selectivity especially for near-native structures. As such, it can be used to select near-native folds generated by structure prediction algorithms as well as for protein structure refinement.     

Distinguish protein decoys by using a scoring function based on a new AMBER force field, short molecular dynamics simulations, and the generalized born solvent model

Recent works have shown the ability of physics-based potentials (e.g., CHARMM and OPLS-AA) and energy minimization to differentiate the native protein structures from large ensemble of non-native structures. In this study, we extended previous work by other authors and developed an energy scoring function using a new set of AMBER parameters (also recently developed in our laboratory) in conjunction with molecular dynamics and the Generalized Born solvent model. We evaluated the performance of our new scoring function by examining its ability to distinguish between the native and decoy protein structures. Here we present a systematic comparison of our results with those obtained with use of other physics-based potentials by previous authors. A total of 7 decoy sets, 117 protein sequences, and more than 41,000 structures were evaluated. The results of our study showed that our new scoring function represents a significant improvement over previously published physics-based scoring functions.     

SHA.LIN评分和S.T.O.N.E评分对经皮肾镜取石术结石清除率的预测价值比较

目的:比较SHA.LIN评分和S.T.O.N.E评分对经皮肾镜取石术结石清除率的预测价值。方法:选择我院于2016年1月-2017年12月期间行经皮肾镜取石术患者67例为研究对象,在术前对所有患者进行SHA.LIN评分和S.T.O.N.E评分。根据手术结果将患者分为结石清除组(n=49)和结石残留组(n=18),对两组患者的一般资料、SHA.LIN评分、S.T.O.N.E评分进行统计对比。采用多因素Logistic回归分析方法分析患者术后结石残留的影响因素。采用绘制ROC曲线的方法分析SHA.LIN评分和S.T.O.N.E评分对结石清除率的预测结果的敏感性和特异性。结果:67例患者术后结石清除者49例、结石残留者18例,结石清除率为73.13%。结石残留组患者手术时间、术中失血量、住院时间、结石最大截面积、最大累积截面积、结石解剖分布肾盂的发生率、受累肾盏数均高于结石清除组,穿刺通道长度低于结石清除组(P0.05)。结石清除组患者的SHA.LIN评分、S.T.O.N.E评分均低于结石残留组(P0.05)。经多因素Logistic回归分析显示,手术时间、术中失血量、SHA.LIN评分、S.T.O.N.E评分、受累肾盏数是结石残留的影响因素(P0.05)。通过绘制ROC曲线可知,SHA.LIN评分的敏感性为91.25%、特异性为89.12%、曲线下面积(AUC)为0.912(95%CI 0.869~0.948);S.T.O.N.E评分的敏感性为78.75%、特异性为84.24%、AUC为0.782(95%CI 0.690~0.871)。结论:经皮肾镜取石术患者结石清除率与SHA.LIN评分、S.T.O.N.E评分明显相关,两种评分系统均能预测患者的结石清除率,但SHA.LIN评分的敏感性、特异性高于S.T.O.N.E评分。     

State of the art of aerobic granulation in continuous flow bioreactors

In the wake of the success of aerobic granulation in sequential batch reactors (SBRs) for treating wastewater, attention is beginning to turn to continuous flow applications. This is a necessary step given the advantages of continuous flow treatment processes and the fact that the majority of full-scale wastewater treatment plants across the world are operated with aeration tanks and clarifiers in a continuous flow mode. As in SBRs, applying a selection pressure, based on differences in either settling velocity or the size of the biomass, is essential for successful granulation in continuous flow reactors (CFRs). CFRs employed for aerobic granulation come in multiple configurations, each with their own means of achieving such a selection pressure. Other factors, such as bioaugmentation and hydraulic shear force, also contribute to aerobic granulation to some extent. Besides the formation of aerobic granules, long-term stability of aerobic granules is also a critical issue to be addressed. Inorganic precipitation, special inocula, and various operational optimization strategies have been used to improve granule long-term structural integrity. Accumulated studies reviewed in this work demonstrate that aerobic granulation in CFRs is capable of removing a wide spectrum of contaminants and achieving properties generally comparable to those in SBRs. Despite the notable research progress made toward successful aerobic granulation in lab-scale CFRs, to the best of our knowledge, there are only three full-scale tests of the technique, two being seeded with anammox-supported aerobic granules and the other with conventional aerobic granules; two other process alternatives are currently in development. Application of settling- or size-based selection pressures and feast/famine conditions are especially difficult to implement to these and similar mainstream systems. Future research efforts needs to be focused on the optimization of the granule-to-floc ratio, enhancement of granule activity, improvement of long-term granule stability, and a better understanding of aerobic granulation mechanisms in CFRs, especially in full-scale applications.     

Using genetic structure data and phylogenetic criteria in attributing prioritization scores for conservation of spontaneous Capparis spinosa L. populations from Tunisia

In Tunisia, the increasing pharmacological demand for spontaneous capers is actually leading to progressive forest overexploitation and genetic erosion of the species that is actually represented by scattered populations. Therefore, inventories with emphasis on the characterization, management and conservation of this medicinal plant are becoming a great need.In this work, genetic and phylogenetic criteria based on isozyme markers were used for the prioritization of spontaneous Capparis spinosa L. populations for conservation according to Vane-Wright and collaborators taxic method.Enzymatic loci varied in their ability to detect variation and population analyses indicated that most of the variation is partitioned between rather than within populations. Fst, gene flow values, PCA and cluster analysis also revealed significant differentiation between all populations.When combing phylogenetic and genetic criteria we were able to prioritize some of the populations for conservation. Therefore, the standardization and the summatory of all indices indicated that the populations Nebeur, Nahli and Dyr rank as a priority for conservation.So far, results of the present study appear to justify the in situ conservation strategy, where core areas completely free from perturbation would be defined for the populations with the highest priority for conservation, with the populations presenting unique alleles. This would guarantee the maintenance of most of the species’ genetic variation. The ex situ conservation management strategy would imply the setting up of specialized nurseries and national collections that are still missing in the country to counteract population fragmentation, demographic loss and genetic erosion threatening such spontaneous populations.     

A nonracial craniofacial perspective on human variation: A(ustralia) to Z(uni)

Dental and craniofacial measurements were collected for 57 samples from Asia, the Pacific, the aboriginal western hemisphere, and Europe. The craniofacial dimensions include many that are not obviously under the control of specific selective forces. Similar configurations for these in different samples should yield indications of recency of common ancestry according to the logic expressed by Darwin and evident in the relationships indicated by nuclear DNA comparisons. Dental dimensions, however, vary according to the length of time that different intensities in selective forces have been in operation. The craniofacial measurements were transformed into C scores and used to generate Euclidean distance dendrograms. When all the material was used to generate a single dendrogram, the European and Amerindian samples sorted into two regionally identifiable clusters, and the Asian and Pacific material sorted into the three clusters identified in separate previous studies: a Mainland Asian cluster, a Jomon-Pacific cluster and an Australo-Melanesian cluster. Since these clusters are based on variation in traits that are basically nonadaptive in nature, no hierarchical ranking is possible. The clusters simply reflect degree of relationship. This technique holds forth the promise of producing a nonracial assessment of the relationships of all the peoples of the world, past and present.     

Full-loop operation and cathodic acidification of a microbial fuel cell operated on domestic wastewater

The present study emphasizes the importance of overcoming proton limitation in a microbial fuel cell operated on domestic wastewater. When the anode-treated effluent was allowed to trickle into the cathodic compartment (full-loop operation), high COD and suspended solids removal efficiencies over 75% and 84%, respectively, were achieved while ensuring substantial and sustainable power generation. Lower removal efficiencies resulted in decreased cell electromotive force caused by excess substrate crossover. By decreasing the pH in the cathodic compartment to values below 2, we were able to further increase the maximum power generation by 180% in batch mode and 380% in continuous mode as compared to a negative control (tap water of pH 7.6). Under the optimized conditions, the internal resistance and electromotive force were 11 Ω and 0.6 V, respectively, which correspond to the state of the art.