Signs, toy models, and the a priori: from Helmholtz to Wittgenstein

The Marburg neo-Kantians argue that Hermann von Helmholtz’s empiricist account of the a priori does not account for certain knowledge, since it is based on a psychological phenomenon, trust in the regularities of nature. They argue that Helmholtz’s account raises the ‘problem of validity’ (Gültigkeitsproblem): how to establish a warranted claim that observed regularities are based on actual relations. I reconstruct Heinrich Hertz’s and Ludwig Wittgenstein’s Bild theoretic answer to the problem of validity: that scientists and philosophers can depict the necessary a priori constraints on states of affairs in a given system, and can establish whether these relations are actual relations in nature. The analysis of necessity within a system is a lasting contribution of the Bild theory. However, Hertz and Wittgenstein argue that the logical and mathematical sentences of a Bild are rules, tools for constructing relations, and the rules themselves are meaningless outside the theory. Carnap revises the argument for validity by attempting to give semantic rules for translation between frameworks. Russell and Quine object that pragmatics better accounts for the role of a priori reasoning in translating between frameworks. The conclusion of the tale, then, is a partial vindication of Helmholtz’s original account.     

NO is necessary and sufficient for egg activation at fertilization

The early steps that lead to the rise in calcium and egg activation at fertilization are unknown but of great interest--particularly with the advent of in vitro fertilization techniques for treating male infertility and whole-animal cloning by nuclear transfer. This calcium rise is required for egg activation and the subsequent events of development in eggs of all species. Injection of intact sperm or sperm extracts can activate eggs, suggesting that sperm-derived factors may be involved. Here we show that nitric oxide synthase is present at high concentration and active in sperm after activation by the acrosome reaction. An increase in nitrosation within eggs is evident seconds after insemination and precedes the calcium pulse of fertilization. Microinjection of nitric oxide donors or recombinant nitric oxide synthase recapitulates events of egg activation, whereas prior injection of oxyhaemoglobin, a physiological nitric oxide scavenger, prevents egg activation after fertilization. We conclude that nitric oxide synthase and nitric-oxide-related bioactivity satisfy the primary criteria of an egg activator: they are present in an appropriate place, active at an appropriate time, and are necessary and sufficient for successful fertilization.     

Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics

Biochemical networks are perturbed both by fluctuations in environmental conditions and genetic variation. These perturbations must be compensated for, especially when they occur during embryonic pattern formation. Complex chemical reaction networks displaying spatiotemporal dynamics have been controlled and understood by perturbing their environment in space and time. Here, we apply this approach using microfluidics to investigate the robust network in Drosophila melanogaster that compensates for variation in the Bicoid morphogen gradient. We show that the compensation system can counteract the effects of extremely unnatural environmental conditions--a temperature step--in which the anterior and posterior halves of the embryo are developing at different temperatures and thus at different rates. Embryonic patterning was normal under this condition, suggesting that a simple reciprocal gradient system is not the mechanism of compensation. Time-specific reversals of the temperature step narrowed down the critical period for compensation to between 65 and 100 min after onset of embryonic development. The microfluidic technology used here may prove useful to future studies, as it allows spatial and temporal regulation of embryonic development.     

Negation scope detection with a conditional random field model

Identifying negation cues and their scope in a text is an important subtask of information extrac-tion that can benefit other natural language processing tasks, including but not limited to medical da-ta mining, relation extraction, question answering and sentiment analysis.The tasks of negation cue and negation scope detection can be treated as sequence labelling problems.In this paper, a system is presented having two components: negation cue detection and negation scope detection.In the first phase, a conditional random field ( CRF) model is trained to detect the negation cues using a lexicon of negation words and some lexical and contextual features.Then, another CRF model is trained to detect the scope of each negation cue identified in the first phase, using basic lexical and contextual features.These two models are trained and tested using the dataset distributed within the*Sem Shared Task 2012 on resolving the scope and focus of negation.Experimental results show that the system outperformed all the systems submitted to this shared task.     

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.     

Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate

Numerous microRNAs (miRNAs) have been discovered in the genomes of higher eukaryotes, and functional studies indicate that they are important during development. However, little is known concerning the function of individual miRNAs. We approached this problem in zebrafish by combining identification of miRNA expression, functional analyses and experimental validation of potential targets. We show that miR-214 is expressed during early segmentation stages in somites and that varying its expression alters the expression of genes regulated by Hedgehog signaling. Inhibition of miR-214 results in a reduction or loss of slow-muscle cell types. We show that su(fu) mRNA, encoding a negative regulator of Hedgehog signaling, is targeted by miR-214. Through regulation of su(fu), miR-214 enables precise specification of muscle cell types by sharpening cellular responses to Hedgehog.     

The impact of economic growth in mortality modelling for selected OECD countries

The health of a population is affected by social, environmental, and economic factors. Pension providers and consultants, insurance companies, government agencies and individuals in the developed world have a vested interest in understanding how the economic growth will impact on the life expectancy of their population. Therefore, changes in death rates may occur due to climate and economic changes. In this study, we extend a previous study into excess deaths as a result of climate change to also provide a comprehensive investigation of the impact of economic changes using annual female and male data for 5 developed OECD countries. We find that there is strong negative relationship between mortality index, and climate and economic proxies. This model shows to provide better fitting and forecasting results both for females and males, and for all countries studied.     

Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase

We identified an autosomal recessive infantile-onset symptomatic epilepsy syndrome associated with developmental stagnation and blindness. Assuming a founder effect in a large Old Order Amish pedigree, we carried out a genome-wide screen for linkage and identified a single region of homozygosity on chromosome 2p12-p11.2 spanning 5.1 cM (maximum lod score of 6.84). We sequenced genes in the region and identified a nonsense mutation in SIAT9, which is predicted to result in the premature termination of the GM3 synthase enzyme (also called lactosylceramide alpha-2,3 sialyltransferase). GM3 synthase is a member of the sialyltransferase family and catalyzes the initial step in the biosynthesis of most complex gangliosides from lactosylceramide. Biochemical analysis of plasma glycosphingolipids confirmed that affected individuals lack GM3 synthase activity, as marked by a complete lack of GM3 ganglioside and its biosynthetic derivatives and an increase in lactosylceramide and its alternative derivatives. Although the relationship between defects in ganglioside catabolism and a range of lysosomal storage diseases is well documented, this is the first report, to our knowledge, of a disruption of ganglioside biosynthesis associated with human disease.