Chromosome-specific segment size alterations are determinants of prognosis in prostate cancer

Currently, risk stratification is the most difficult problem in prostate cancer (PCa) management. Gleason grading cannot adequately predict cancer progression. This study aimed to identify chromosome-specific segment size alterations that could aid risk stratification and predict metastasis using a retrospective cohort-study strategy. A binary logistic regression model was generated using 16 chromosome-specific segments with size alterations (deletions and amplifications) that showed associations with disease stage (primary versus metastatic). The regression model was trained with the MSKCC PIK3R1 PCa cohort (n = 1417), and validated with the TCGA Firehose Legacy (n = 500), MSKCC Prostate Oncogenome Project (n = 218), and the SU2C/PCF Dream Team (n = 150) PCa cohorts. Furthermore, the capacity of the model to predict metastasis between primary tumours with metastasis (n = 54) and primary tumours without metastasis (n = 54) was tested. The accuracy, sensitivity, and specificity of the model at disease stage stratification ranged from 69.02% to 88.55%, 72.8% to 86.00% and 66.30% to 89.50%, respectively. The model also showed good performance at metastasis prediction with accuracy, sensitivity, and specificity of 57.41%, 62.96% and 51.85%, respectively. The study conclusion was that chromosome-specific segment size alterations can aid risk stratification and metastasis prediction. The significance of the study findings is that in combinations with clinical, biochemical, and histopathological variables, chromosome-specific alterations could improve current risk stratification and prediction models for PCa.     

A Generalized Logistic Model for Quantal Response Bioassay

In bioassay, where different levels of the stimulus may represent different doses of a drug, the binary response is the death or survival of an individual receiving a specified dose. In such applications, it is common to model the probability of a positive response P at the stimulus level x by P = F(x′β), where F is a cumulative distribution function and β is a vector of unknown parameters which characterize the response function. The two most popular models used for modelling binary response bioassay involve the probit model [BLISS (1935), FINNEY (1978)], and the logistic model [BERKSON (1944), BROWN (1982)]. However, these models have some limitations. The use of the probit model involves the inverse of the standard normal distribution function, making it rather intractable. The logistic model has a simple form and a closed expression for the inverse distribution function, however, neither the logistic nor the probit can provide a good fit to response functions which are not symmetric or are symmetric but have a steeper or gentler incline in the central probability region. In this paper we introduce a more realistic model for the analysis of quantal response bioassay. The proposed model, which we refer to it as the generalized logistic model, is a family of response curves indexed by shape parameters m₁ and m₂. This family is rich enough to include the probit and logistic models as well as many others as special cases or limiting distributions. In particular, we consider the generalized logistic three parameter model where we assume that m₁ = m, m is a positive real number, and m₂ = 1. We apply this model to various sets of data, comparing the fit results to those obtained previously by other dose-response curves such as the logistic and probit, and showing that the fit can be improved by using the generalized logistic.     

Age and social experience induced plasticity across brain regions of the paper wasp Polistes fuscatus

Developmental studies of brain volumes can reveal which portions of neural circuits are sensitive to environmental inputs. In social insects, differences in relative investment across brain regions emerge as behavioural repertoires change during ontogeny or as a result of experience. Here, we test the effects of maturation and social experience on morphological brain development in Polistes fuscatus paper wasps, focusing on brain regions involved in visual and olfactory processing. We find that mature wasps regardless of social experience have relatively larger brains than newly emerged wasps and this difference is driven by changes to mushroom body calyx and visual regions but not olfactory processing neuropils. Notably, social wasps invest more in the anterior optic tubercle (AOT), a visual glomerulus involved in colour and object processing in other taxa, relative to other visual integration centres the mushroom body calyces compared with aged socially naive wasps. Differences in developmental plasticity between visual and olfactory neuropil volumes are discussed in light of behavioural maturation in paper wasps, especially as it relates to social recognition. Previous research has shown that P. fuscatus need social experience to develop specialized visual processing of faces, which is used to individually recognize conspecifics. The present study suggests that the AOT is a candidate brain region that could mediate facial processing in this species.     

Whole exome sequencing,in silico and functional studies confirm the association of the GJB2 mutation p.Cys169Tyr with deafness and suggest a role for the TMEM59 gene in the hearing process

The development of next generation sequencing techniques has facilitated the detection of mutations at an unprecedented rate. These efficient tools have been particularly beneficial for extremely heterogeneous disorders such as autosomal recessive non-syndromic hearing loss, the most common form of genetic deafness. GJB2 mutations are the most common cause of hereditary hearing loss. Amongst them the NM_004004.5: c.506G > A (p.Cys169Tyr) mutation has been associated with varying severity of hearing loss with unclear segregation patterns. In this study, we report a large consanguineous Emirati family with severe to profound hearing loss fully segregating the GJB2 missense mutation p.Cys169Tyr. Whole exome sequencing (WES), in silico, splicing and expression analyses ruled out the implication of any other variants and confirmed the implication of the p.Cys169Tyr mutation in this deafness family. We also show preliminary murine expression analysis that suggests a link between the TMEM59 gene and the hearing process. The present study improves our understanding of the molecular pathogenesis of hearing loss. It also emphasizes the significance of combining next generation sequencing approaches and segregation analyses especially in the diagnosis of disorders characterized by complex genetic heterogeneity.     

Interdependence between neuroendocrine programming and the generation of immune recognition in ontogeny

Sequential, chronologically, and quantitatively critical inoculation of different allogeneic hybrid cells into mice during the neonatal and perinatal period results in an indefinite prolongation of the perinatal stage during which tolerance can be readily induced. Consequently, a permanent specific tolerance to the sequentially inoculated alloantigens and a parallel alteration and retardation in the maturation of the developing endocrine system which normally controls immune differentiation are observed. The endocrine and immune parameters are altered only when the successive presentation of alloantigens is begun at birth, as this is a critical stage of development at which both the neuroendocrine (hypothalamic-pituitary) and the thymo-lymphatic systems are still highly undifferentiated. The phylogenetically and ontogenetically interlocked and interdependent thymo-lymphatic and neuroendocrine networks thus constitute a basic homoeostatic regulatory system in which signals of both endocrine and antigenic nature are detected and elaborated with consequent proper response in a homeostatic fashion. On the basis of these considerations and the experimental findings that support them, the generation of tolerance and immunity (recognition of self and nonself components of the body) appears to be a part of the definitive brain programming for neuroendocrine and immune functions in early ontogey. This would constitute an augmented interpretation of the concept of immune tolerance as “specific central failure of the mechanisms of response” originally put forth by Medawar (1956, Proc. Roy. Soc.146B, 1).     

Influence of Long Term Irrigation with Pulp and Paper Mill Effluent on the Bacterial Community Structure and Catabolic Function in Soil

Microbial communities play a vital role in maintaining soil health. A multiphasic approach to assess the effect of pulp and paper mill effluent on both the structure and function of microbial soil communities is taken. Bacterial communities from agricultural soils irrigated with pulp and paper mill effluent were compared to communities form soils irrigated with well water. Samples were taken from fields in the state of Uttarakhand, India, where pulp and paper mill effluent has been used for irrigation for over 25 years. Comparisons of bacterial community structure were conducted using sequencing of the 16S rRNA gene from both isolates and clone libraries attained from the soil. Community-level physiological profiling was used to characterize the functional diversity and catabolic profile of the bacterial communities. The multiphasic approach using both physiological and molecular techniques proved to be a powerful tool in evaluating the soil bacterial community population and population differences therein. A significant and consistent difference in the population structure and function was found for the bacterial communities from soil irrigated with effluent in comparison to fields irrigated with well water. The diversity index parameters indicated that the microbial community in pulp and paper mill effluent irrigated fields were more diverse in both structure and function. This suggests that the pulp and paper mill effluent is not having a negative effect on the soil microbial community, but in fact may have a positive influence. In terms of soil health, this finding supports the continued use of pulp and paper mill effluent for irrigation. This is however only one aspect of soil health which was evaluated. Further studies on soil resistance and robustness could be undertaken to holistically evaluate soil health in this situation.     

Binary synthesis of multicomponent peptide mixtures by the portioning–mixing technique

By introducing a new operation (non-coupling), our portioning–mixing method has become suitable for preparing binary peptide libraries. We demonstrate that all the expected components of a simple library are present in the mixture. The number of components in such libraries, the molar ratio of peptides as well as the possibilities of screening are discussed.