Kepler: Analogies in the search for the law of refraction

This paper examines the methodology used by Kepler to discover a quantitative law of refraction. The aim is to argue that this methodology follows a heuristic method based on the following two Pythagorean principles: (1) sameness is made known by sameness, and (2) harmony arises from establishing a limit to what is unlimited. We will analyse some of the author's proposed analogies to find the aforementioned law and argue that the investigation's heuristic pursues such principles.     

Molecular parasitology: progress towards the development of vaccines for malaria, filariasis, and schistosomiasis

Advances in molecular biology have allowed for the identification of potential vaccine candidates against several parasitic diseases. Antigens from various life stages of Plasmodium and Schistosoma species and filarial worms have been cloned, sequenced and tested as vaccines. Results to date in animal models have been promising. Modest levels of protection against experimental human malaria have been obtained using both sporozoite and blood-stage antigens. However, a greater understanding of the mechanisms which lead to immunity against parasites is required before effective vaccines can be developed.     

Molecular parasitology: Progress towards the development of vaccines for malaria,filariasis, and schistosomiasis

Summary Advances in molecular biology have allowed for the identification of potential vaccine candidates against several parasitic diseases. Antigens from various life stages ofPlasmodium andSchistosoma species and filarial worms have been cloned, sequenced and tested as vaccines. Results to date in animal models have been promising. Modest levels of protection against experimental human malaria have been obtained using both sporozoite and blood-stage antigens. However, a greater understanding of the mechanisms which lead to immunity against parasites is required before effective vaccines can be developed.     

Comparison of prospective Hawkes and recursive point process models for Ebola in DRC

Point process models, such as Hawkes and recursive models, have recently been shown to offer improved accuracy over more traditional compartmental models for the purposes of modeling and forecasting the spread of disease epidemics. To explicitly test the performance of these two models in a real-world and ongoing epidemic, we compared the fit of Hawkes and recursive models to outbreak data on Ebola virus disease (EVD) in the Democratic Republic of the Congo in 2018–2020. The models were estimated, and the forecasts were produced, time-stamped, and stored in real time, so that their prospective value can be assessed and to guard against potential overfitting. The fit of the two models was similar, with both models resulting in much smaller errors in the beginning and waning phases of the epidemic and with slightly smaller error sizes on average for the Hawkes model compared with the recursive model. Our results suggest that both Hawkes and recursive point process models can be used in near real time during the course of an epidemic to help predict future cases and inform management and mitigation strategies.     

The search for the right partner: Homologous pairing and DNA strand exchange proteins in eukaryotes

Finding the right partner is a central problem in homologous recombination. Common to all models for general recombination is a homologous pairing and DNA strand exchange step. In prokaryotes this process has mainly been studied with the RecA protein ofEscherichia coli. Two approaches have been used to find homologous pairing and DNA strand exchange proteins in eukaryotes. A biochemical approach has resulted in numerous proteins from various organisms. Almost all of these proteins are biochemically fundamentally different from RecA. The in vivo role of these proteins is largely not understood. A molecular-genetical approach has identified structural homologs to theE. coli RecA protein in the yeastSaccharomyces cerevisiae and subsequently in other organisms including other fungi, mammals, birds, and plants. The biochemistry of the eukaryotic RecA homologs is largely unsolved. For the fungal RecA homologs (S. cerevisiae RAD51, RAD55, RAD57, DMC1; Schizosaccharomyces pombe rad51; Neurospora crassa mei3) a role in homologous recombination and recombinational repair is evident. Besides recombination, homologous pairing proteins might be involved in other cellular processes like chromosome pairing or gene inactivation.     

Towards progress on DNA vaccines for cancer

Cancer immunotherapy faces many obstacles that include eliciting immune reactions to self antigens as well as overcoming tumor-derived immunosuppressive networks and evasion tactics. Within the vaccine arsenal for inhibiting cancer proliferation, plasmid DNA represents a novel immunization strategy that is capable of eliciting both humoral and cellular arms of the immune response in addition to being safely administered and easily engineered and manufactured. Unfortunately, while DNA vaccines have performed well in preventing and treating malignancies in animal models, their overall application in human clinical trials has not impacted cancer regression to date. Since the establishment of these early trials, progress has been made in terms of increasing DNA vaccine immunogenicity and subverting the suppressive properties of tumor cells. Therefore, the success of future plasmid DNA use in cancer patients will depend on combinatorial strategies that enhance and direct the DNA vaccine immune response while also targeting tumor evasion mechanisms. Received 2 April 2007; received after revision 14 May 2007; accepted 21 May 2007     

The search for migraine genes: an overview of current knowledge

Migraine is a complex familial condition that imparts a significant burden on society. There is evidence for a role of genetic factors in migraine, and elucidating the genetic basis of this disabling condition remains the focus of much research. In this review we discuss results of genetic studies to date, from the discovery of the role of neural ion channel gene mutations in familial hemiplegic migraine (FHM) to linkage analyses and candidate gene studies in the more common forms of migraine. The success of FHM regarding discovery of genetic defects associated with the disorder remains elusive in common migraine, and causative genes have not yet been identified. Thus we suggest additional approaches for analysing the genetic basis of this disorder. The continuing search for migraine genes may aid in a greater understanding of the mechanisms that underlie the disorder and potentially lead to significant diagnostic and therapeutic applications. Received 16 December 2005; received after revision 9 October 2006; accepted 13 November 2006     

Towards a science of the individual: the Aristotelian search for scientific knowledge of individual entities

This article seeks to take a step towards recognizing that science can deal with the concrete and individual as well as the universal. I shall concentrate on some of Aristotle’s texts, as there is a long tradition going back to Aristotle, according to which science deals only with the universal, although his work also contains texts of a very different tenor. He tries to improve the process of definition as an attempt to bring science closer to the concrete, but ends up realizing that there are some unreachable limits. There is, however, a second Aristotelian approach to the problem in Metaphysica M 10, a passage which takes scientific rapprochement to the individual further by introducing a distinction between science in potential and science in act. The former is universal, but the latter deals with individual substances and processes. Aristotle himself acknowledges here that in one sense science is universal and in another it is not, a position that raises important ontological and epistemological problems. Some suggestions are also offered concerning the kind of truth applicable to science in act, that is, practical truth.     

Of volatiles and peptides: in search for MHC-dependent olfactory signals in social communication

Genes of the major histocompatibility complex (MHC), which play a critical role in immune recognition, are considered to influence social behaviors in mice, fish, humans, and other vertebrates via olfactory cues. As studied most extensively in mice, the polymorphism of MHC class I genes is considered to bring about a specific scent signature, which is decoded by the olfactory system resulting in an individual-specific reaction such as mating. On the assumption that this signature resides in volatiles, extensive attempts to identify these MHC-specific components in urine failed. Alternatively, it has been suggested that peptide ligands of MHC class I molecules are released into urine and can elicit an MHC-haplotype-specific behavioral response after uptake into the nose by sniffing. Analysis of the urinary peptide composition of mice shows that MHC-derived peptides are present, albeit in extremely low concentrations. In contrast, urine contains abundant peptides which differ between mouse strains due to genomic variations such as single-nucleotide variations or complex polymorphisms in multigene families as well as in their concentration. Thus, urinary peptides represent a real-time sampling of the expressed genome available for sensory evaluation. It is suggested that peptide variation caused by genomic differences contains sufficient information for individual recognition beyond or instead of an influence of the MHC in mice and other vertebrates.     

Botulinum toxin as a carrier for oral vaccines

Botulinum toxin is an unusually potent substance that acts on the nervous system to produce the clinical outcome of flaccid paralysis. To produce this effect, the toxin ordinarily proceeds through two separate but essential sequences of events. During the first, the toxin is ingested, it traverses a portion of the gastrointestinal system and then it is transcytosed from the lumen of the gut to the general circulation. During the second, circulating toxin binds to peripheral cholinergic nerve endings, it is endocytosed and then it acts as a metalloendoprotease to cleave polypeptides that are essential for exocytosis. Although botulinum toxin is antigenic, it ordinarily does not evoke an immune response during or after cases of oral poisoning. This is due to the fact that the dose of toxin that produces flaccid paralysis—and potentially death—is less than the dose needed to evoke an antibody response. In the recent past, the techniques of molecular biology have been used to generate an expression product of botulinum toxin that retains the ability to escape the gut and reach the general circulation, retains the ability to evoke an immune response, but has lost the ability to produce neurotoxicity. This modified toxin may have two clinical applications. The expression product itself may have utility as an oral vaccine against botulism. Beyond this, the modified toxin, or a truncation mutant of the toxin, may have utility as a carrier in the construction of other oral vaccines. Both potential applications could lead to the expression of oral vaccines in common foods. Received 29 December 1998; received after revision 22 March 1999; accepted 24 March 1999     

Reduction of the number of mice used for potency testing of human and animal rabies vaccines

Eight different rabies vaccines were tested for their potency in the standard mouse potency test using 3-, 5- and 7-week-old mice. 5-week-old mice seem to be best suited for this purpose, variability from test to test could be reduced considerably. An ELISA was used in parallel for the evaluation of the rabies glycoprotein content of rabies vaccines. Results of the mouse potency test correlated well with those of the ELISA if highly purified human vaccines were tested. Unspecific reactions in the ELISA caused by adjuvanted veterinary vaccines could not be blocked. Further experiments will be needed in order to evaluate the potency of inactivated veterinary rabies vaccines by a in vitro test.     

Reduction of the number of mice used for potency testing of human and animal rabies vaccines

Summary Eight different rabies vaccines were tested for their potency in the standard mouse potency test using 3-, 5- and 7-week-old mice. 5-week-old mice seem to be best suited for this purpose, variability from test to test could be reduced considerably. An ELISA was used in parallel for the evaluation of the rabies glycoprotein content of rabies vaccines. Results of the mouse potency test correlated well with those of the ELISA if highly purified human vaccines were tested. Unspecific reactions in the ELISA caused by adjuvanted veterinary vaccines could not be blocked. Further experiments will be needed in order to evaluate the potency of inactivated veterinary rabies vaccines by a in vitro test.