Semmelweis' discovery and its Finnish follow-up

Professor Ignác Semmelweis (1818-1865) is one of the great personalities of medical history. He insisted on washing hands with chlorine water before any obstetrical intervention, he was the first to demonstrate its importance in preventing puerperal fever. Thus, the principle of asepsis was introduced prior to the discovery of bacteria and bacterial diseases. Semmelweis carefully documented his findings and in this way pioneered the scientific analysis of clinical data Medical community of that time misinterpreted Semmelweis' great ideas, he died abandoned and forgotten. A Finnish doctor Josef Adam Joachim Pippingsk?ld was one of the first obstetricians who had realized the importance of Semmelweis' work. In 1861, in his letter to Semmelweis he reported about his own findings and favorable results in prevention of puerperal fever in Helsinki. Two decades earlier, Dr. Ehrstr?m in the University of Helsinki had submitted his thesis on pathophysiology of puerperal fever that was similar to the ideas of Semmelweis. Long before modern times in Finland, mothers traditionally had their babies delivered in smoke saunas, where heating and smoke of bactericidal phenols created a clean, rather aseptic environment. Hand washing was self-evident necessity. However, the situation was quite different in the Central European universities and departments of obstetrics, where the medical training and clinical practice took place side by side. Semmelweis' life and his contribution to medicine was appreciated even in the theatrical circles of Finland. The piece "Semmelweis" of Norwegian playwright Jens Bj?rneboe got its World Premier in the Swedish Theatre in Turku, former capital of Finland, in September 1969.     

The discovery of adenosine triphosphate and the establishment of its structure

The discovery of adenosine triphosphate and the establishment of its structure     

Chemical proteomics and its impact on the drug discovery process

Despite the rapid growth of postgenomic data and fast-paced technology advancement, drug discovery is still a lengthy and difficult process. More effective drug design requires a better understanding of the interaction between drug candidates and their targets/off-targets in various situations. The ability of chemical proteomics to integrate a multiplicity of disciplines enables the direct analysis of protein activities on a proteome-wide scale, which has enormous potential to facilitate drug target elucidation and lead drug verification. Over recent years, chemical proteomics has experienced rapid growth and provided a valuable method for drug target identification and inhibitor discovery. This review introduces basic concepts and technologies of different popular chemical proteomic approaches. It also covers the essential features and recent advances of each approach while underscoring their potentials in drug discovery and development.     

Chemical proteomics and its application to drug discovery

The completion of the human genome sequencing project has provided a flood of new information that is likely to change the way scientists approach the study of complex biological systems. A major challenge lies in translating this information into new and better ways to treat human disease. The multidisciplinary science of chemical proteomics can be used to distill this flood of new information. This approach makes use of synthetic small molecules that can be used to covalently modify a set of related enzymes and subsequently allow their purification and/or identification as valid drug targets. Furthermore, such methods enable rapid biochemical analysis and small-molecule screening of targets thereby accelerating the often difficult process of target validation and drug discovery.     

The epistellar body and what followed from its discovery

The sequence of discoveries that has followed the investigation of this small yellow spot shows the value of studies begun out of "mere curiosity". The spot occurs on the stellate ganglion of octopods. It proved to be an enclosed sac, perhaps a gland. The search for it in squids and cuttlefishes led to the discovery of the giant nerve fibres. At first they were thought to be veins but we soon showed that they were nerve fibres concerned with jet propulsion. Their action potentials, membranes and synapses have been used for thousand of studies, including those that led to the Hodkin Huxley equations. They have been the basis of much of modern neuroscience. The epistellar body itself proved not to be a gland but a photoreceptor. Comparable photosensitive vesicles are especially large in the heads of deep-sea squids. In the mesopelagic ones they allow the squid to conceal itself by counterillumination, matching its own light output to the light coming from above. In bathypelagic squids the vesicles are enormous and probably keep the animals in the dark, where they breed. The function of the epistellar body, lying within the mantle of octopods is still unknown. It may act in the transparent larval stage to trigger the ejection of luminous plankton, which would be a hazard.     

Acanthoparyphium tyosenense: the discovery of human infection and identification of its source

Acanthoparyphium tyosenense Yamaguti, 1939 (Digenea: Echinostomatidae), was originally reported as an avian intestinal parasite; here, its presence is reported in 10 humans in the Republic of Korea. The patients were 9 adults aged 35-66 yr (males and females) and a young girl aged 7 yr residing in 2 coastal villages in Puan-gun, Chollabuk-do. The worms were recovered after treatment with praziquantel and purgation with magnesium salts. A total of 158 specimens (1-107 specimens/individual) was collected, together with varying numbers of other intestinal flukes. The patients had eaten various kinds of brackish water mollusks caught in an estuary near their villages. Five bivalves and a gastropod species suspected as sources of human infection were collected and examined. Two bivalves (Mactra veneriformis and Solen grandis) and the gastropod (Neverita bicolor) were found to be infected with the metacercariae of A. tyosenense; adult flukes were confirmed after the experimental infection of chicks. The results show that A. tyosenense infects humans and that brackish water mollusks are the source of human infection.     

Targeted proteomics on its way to discovery

For a long time, targeted and discovery proteomics covered different corners of the detection spectrum, with targeted proteomics focused on small target sets. This changed with the recent advances in highly multiplexed analysis. While discovery proteomics still pushes higher numbers of identified and quantified proteins, the advances in targeted proteomics rose to cover large parts of less complex proteomes or proteomes with low protein detection counts due to dynamic range restrictions, like the blood proteome. These new developments will impact, especially on the field of biomarker discovery and the possibility of using targeted proteomics for diagnostic purposes.     

A bioassay-driven discovery of an unexpected selenophene and its cytotoxicity

During the reaction of methyl 3β-acetoxy-glycyrrhetinate (1) with SeO₂ significant amounts of a cytotoxic hitherto unprecedented triterpenoic selenophene 3 are formed. This compound stops cell proliferation and acts by apoptosis.     

Ecological studies of polyploidy in the 100 years following its discovery

Polyploidy is a mutation with profound phenotypic consequences and thus hypothesized to have transformative effects in plant ecology. This is most often considered in the context of geographical and environmental distributions—as achieved from divergence of physiological and life-history traits—but may also include species interactions and biological invasion. This paper presents a historical overview of hypotheses and empirical data regarding the ecology of polyploids. Early researchers of polyploidy (1910s–1930s) were geneticists by training but nonetheless savvy to its phenotypic effects, and speculated on the importance of genome duplication to adaptation and crop improvement. Cytogenetic studies in the 1930s–1950s indicated that polyploids are larger (sturdier foliage, thicker stems and taller stature) than diploids while cytogeographic surveys suggested that polyploids and diploids have allopatric or parapatric distributions. Although autopolyploidy was initially regarded as common, influential writings by North American botanists in the 1940s and 1950s argued for the principle role of allopolyploidy; according to this view, genome duplication was significant for providing a broader canvas for hybridization rather than for its phenotypic effects per se. The emphasis on allopolyploidy had a chilling effect on nascent ecological work, in part due to taxonomic challenges posed by interspecific hybridization. Nonetheless, biosystematic efforts over the next few decades (1950s–1970s) laid the foundation for ecological research by documenting cytotype distributions and identifying phenotypic correlates of polyploidy. Rigorous investigation of polyploid ecology was achieved in the 1980s and 1990s by population biologists who leveraged flow cytometry for comparative work in autopolyploid complexes. These efforts revealed multi-faceted ecological and phenotypic differences, some of which may be direct consequences of genome duplication. Several classical hypotheses about the ecology of polyploids remain untested, however, and allopolyploidy—regarded by most botanists as the primary mode of genome duplication—is largely unstudied in an ecological context.     

Proteomics and its applications for biomarker discovery in human saliva

Human saliva is a biological fluid with enormous diagnostic potential. Because saliva can be non-invasively collected, it provides an attractive alternative for blood, serum or plasma. It has been postulated that the blood concentrations of many components are reflected in saliva. Saliva harbors a wide array of proteins, which can be informative for the detection of diseases. Profiling the proteins in saliva over the course of disease progression could reveal potential biomarkers indicative of different stages of diseases, which may be useful in medical diagnostics. With advanced instrumentation and developed refined analytical techniques, proteomics is widely envisioned as a useful and powerful approach for salivary proteomic biomarker discovery. As proteomic technologies continue to mature, salivary proteomics have great potential for biomarker research and clinical applications. The progress and current status of salivary proteomics and its application in the biomarker discovery of oral and systematic diseases will be reviewed. The scientific and clinical challenges underlying this approach will also be discussed.     

Proteomics and its applications for biomarker discovery in human saliva

Human saliva is a biological fluid with enormous diagnostic potential. Because saliva can be non-invasively collected, it provides an attractive alternative for blood, serum or plasma. It has been postulated that the blood concentrations of many components are reflected in saliva. Saliva harbors a wide array of proteins, which can be informative for the detection of diseases. Profiling the proteins in saliva over the course of disease progression could reveal potential biomarkers indicative of different stages of diseases, which may be useful in medical diagnostics. With advanced instrumentation and developed refined analytical techniques, proteomics is widely envisioned as a useful and powerful approach for salivary proteomic biomarker discovery. As proteomic technologies continue to mature, salivary proteomics have great potential for biomarker research and clinical applications. The progress and current status of salivary proteomics and its application in the biomarker discovery of oral and systematic diseases will be reviewed. The scientific and clinical challenges underlying this approach will also be discussed.     

Identification of melanin-concentrating hormone receptor and its impact on drug discovery

The neuropeptide melanin-concentrating hormone (MCH) was originally isolated from the pituitary of salmon, in which it causes skin paling. MCH is also found abundantly in mammalian neurons, and has been detected in the lateral hypothalamus and zona incerta, brain regions that are at the center of feeding behavior. Acute central administration of MCH leads to a rapid and significant increase in food intake, while MCH expression changes in states of altered energy balance, such as fasting and obesity. Furthermore, MCH knockout mice tend toward hypophagia and leanness. In 1999, we and four other groups identified an orphan G-protein-coupled receptor (GPCR) as a specific receptor for MCH (MCH-1 receptor). Although a second MCH receptor (MCH-2 receptor) was isolated in humans, it was found to be non-functional or encode a non-functional pseudogene in non-human species, including rodents. The discovery of these MCH receptors permitted the launch of a broad array of drug screening efforts and three MCH-1 receptor antagonists were identified to reduce food intake and body weight. Interestingly, some antagonists unexpectedly produced evidence that blockade of these receptors has antidepressant and anxiolytic activities. The expressions of the MCH receptors, which have been implicated in regulating emotion, stress and motivation, make MCH an excellent candidate for integrating the various homeostatic stimuli necessary for maintaining the proper conditions of energy metabolism and other physiological functions. Finally, the speed at which MCH receptor studies have been undertaken exemplifies the impact that this deorphanized GPCR will have on setting the stage for more detailed physiological studies.     

Immonium ion scanning for the discovery of post-translational modifications and its application to histones

This study investigates the use of immonium ion scanning for the discovery of methylated and acetylated peptides. Tandem mass spectrometry of modified and unmodified versions of identical peptides revealed ions of 98, 112 and 126 m/ z specifically in association with mono-, dimethylated and acetylated lysine, respectively. Ions of 143 m/ z were seen to be associated with monomethylated arginine, although were not unique to this amino acid. Use of immonium ion scanning with differing collision energies (35, 55, 75, 95, 115 eV) showed that where immonium ions are strong and unique for a modified amino acid, the discovery rate of modified peptides can be improved up to 4-fold over control analyses. The position of an amino acid in a peptide, being terminal or internal, also affected the efficiency of identification of modified peptides. Higher collision energy scanning was required for the most effective identification of peptides with internal modified residues. We conclude that immonium ion scanning, particularly with a range of collision energies, can improve the discovery efficiency of post-translational modifications in peptides.     

Phage-based target discovery and its exploitation towards novel antibacterial molecules

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