From protein structure to biochemical function?

Here we describe various methods currently under development aimed at identifying a proteins function from its three-dimensional structure. We are combining a number of these methods to create a pipeline of applications, called ProFunc, which will take a given 3D structure, run all the applications on it and compile and summarise the results obtained. The aim is to provide a best guess as to the proteins function from the evidence provided by the different methods. Here we present three examples, using structures solved by the Midwest Center for Structural Genomics consortium, illustrating the strengths and weaknesses of current approaches.     

Editorial. Peptides – From Discovery to Therapeutics

International Journal of Peptide Research and Therapeutics -     

The biological regulation of sea urchin larval skeletogenesis – From genes to biomineralized tissue

Biomineralization is the process in which soft organic tissues use minerals to produce shells, skeletons and teeth for various functions such as protection and physical support. The ability of the cells to control the time and place of crystal nucleation as well as crystal orientation and stiffness is far beyond the state-of-the art of human technologies. Thus, understanding the biological control of biomineralization will promote our understanding of embryo development as well as provide novel approaches for material engineering. Sea urchin larval skeletogenesis offers an excellent platform for functional analyses of both the molecular control system and mineral uptake and deposition. Here we describe the current understanding of the genetic, molecular and cellular processes that underlie sea urchin larval skeletogenesis. We portray the regulatory genes that define the specification of the skeletogenic cells and drive the various morphogenetic processes that occur in the skeletogenic lineage, including: epithelial to mesenchymal transition, cell migration, spicule cavity formation and mineral deposition into the spicule cavity. We describe recent characterizations of the size, motion and mineral concentration of the calcium-bearing vesicles in the skeletogenic cells. We review the distinct specification states within the skeletogenic lineage that drive localized skeletal growth at the tips of the spicules. Finally, we discuss the surprising similarity between the regulatory network and cellular processes that drive sea urchin skeletogenesis and those that control vertebrate vascularization. Overall, we illustrate the novel insights on the biological regulation and evolution of biomineralization, gained from studies of the sea urchin larval skeletogenesis.     

Urocortin – From Parkinson's disease to the skeleton

Urocortin (Ucn 1), a 40 amino acid long peptide related to corticotropin releasing factor (CRF) was discovered 19 years ago, based on its sequence homology to the parent molecule. Its existence was inferred in the CNS because of anatomical and pharmacological discrepancies between CRF and its two receptor subtypes. Although originally found in the brain, where it has opposing actions to CRF and therefore confers stress-coping mechanisms, Ucn 1 has subsequently been found throughout the periphery including heart, lung, skin, and immune cells. It is now well established that this small peptide is involved in a multitude of physiological and pathophysiological processes, due to its receptor subtype distribution and promiscuity in second messenger signalling pathways. As a result of extensive studies in this field, there are now well over one thousand peer reviewed publications involving Ucn 1. In this review, we intend to highlight some of the less well known actions of Ucn 1 and in particular its role in neuronal cell protection and maintenance of the skeletal system, both by conventional methods of reviewing the literature and using bioinformatics, to highlight further associations between Ucn 1 and disease conditions. Understanding how Ucn 1 works in these tissues, will help to unravel its role in normal and pathophysiological processes. This would ultimately allow the generation of putative medical interventions for the alleviation of important diseases such as Parkinson's disease, arthritis, and osteoporosis.     

Introduction to the thematic issue “From brain function to therapy”

<正>This thematic issue of Science China Life Sciences,"From brain function to therapy",highlights some of the exciting research being undertaken in the Joint Laboratory of Neuroscience and Cognition,an international scientific collaboration between the Queensland Brain Institute(QBI)at The     

The discovery of Rubisco activase – yet another story of serendipity

A brief history of Rubisco (ribulose bisphosphate carboxylase oxygenase) research and the events leading to the discovery and initial characterization of Rubisco activase are described. Key to the discovery was the chance isolation of a novel Arabidopsis photosynthesis mutant. The characteristics of the mutant suggested that activation of Rubisco was not a spontaneous process in vivo, but involved a heritable factor. The search for the putative factor by 2D electrophoresis identified two polypeptides, genetically linked to Rubisco activation, that were missing in chloroplasts from the mutant. An assay for the activity of these polypeptides, which were given the name Rubisco activase, was developed after realizing the importance of including ribulose bisphosphate (RuBP) in the assay. The requirement for ATP and the subsequent identification of activase as an ATPase came about fortuitously, the result of a RuBP preparation that was contaminated with adenine nucleotides. Finally, the ability of activase to relieve inhibition of the endogenous Rubisco inhibitor, 2-carboxyarabinitol 1-phosphate, provided an early indication of the mechanism by which activase regulates Rubisco. This revised version was published online in June 2006 with corrections to the Cover Date.     

The diversity of ACBD proteins – From lipid binding to protein modulators and organelle tethers

Members of the large multigene family of acyl-CoA binding domain containing proteins (ACBDs) share a conserved motif required for binding of Coenzyme A esterified fatty acids of various chain length. These proteins are present in the three kingdoms of life, and despite their predicted roles in cellular lipid metabolism, knowledge about the precise functions of many ACBD proteins remains scarce. Interestingly, several ACBD proteins are now suggested to function at organelle contact sites, and are recognized as host interaction proteins for different pathogens including viruses and bacteria. Here, we present a thorough phylogenetic analysis of the ACBD family and discuss their structure and evolution. We summarize recent findings on the various functions of animal and fungal ACBDs with particular focus on peroxisomes, the role of ACBD proteins at organelle membranes, and their increasing recognition as targets for pathogens.     

From septicemia to sepsis 3.0 – from Ignaz Semmelweis to Louis Pasteur

Sepsis remains a contemporary threat, and its frequency remains high amongst an aging population. Its definition has been regularly revisited, but the impact of the translational research studying it remains very modest compared to the results seen after the introduction of hygiene and the use of antibiotics. In the past, the main forms of sepsis were hospital gangrene (also known as nosocomial fever or putrid fever) that affected the wounded, and puerperal fever that affected women shortly after delivery. In 1858, Armand Trousseau stated that these two pathologies were identical. Lucrezia Borgia, who died in 1519, is undoubtedly the most famous woman to die from puerperal fever. The notion of sepsis as a real epidemic was deplored. For decades doctors remained deaf to the recommendations of their clairvoyant colleagues who advocated for the use of hygienic measures. It was as early as 1795 that Alexander Gordon (UK) and later in 1843, Oliver Holmes (USA), called for the use of hygienic practices. In 1847, Ignaz Semmelweis, a Hungarian physician, provided an irrefutable demonstration of the importance of hygiene in the prevention of contamination by the hands of the practitioners. But Ignaz Semmelweis' life was a tragedy, his fight against the medical nomenklatura was a tragedy, and his death was a tragedy! Nowadays, Ignaz Semmelweis is receiving the honor that he deserves, but never received during his life. Carl Mayrhofer, Victor Feltz, and Léon Coze were the first to associate the presence of bacteria with sepsis. These observations were confirmed by Louis Pasteur who, thanks to his prestige, had a great influence on how to undertake measures to prevent infections. He inspired Joseph Lister who reduced mortality associated with surgery, particularly amputation, by utilizing antiseptic methods.     

RANKL/RANK – From bone physiology to breast cancer

RANK and its ligand RANKL are key molecules in bone metabolism and are critically involved in pathologic bone disorders. Deregulation of the RANK/RANKL system is for example a main reason for the development of postmenopausal osteoporosis, which affects millions of women worldwide. Another essential function of RANK and RANKL is the development of a functional lactating mammary gland during pregnancy. Sex hormones, in particular progesterone, induce RANKL expression resulting in proliferation of mammary epithelial cells. Moreover, RANK and RANKL have been shown to regulate mammary epithelial stem cells. RANK and RANKL were also identified as critical mechanism in the development of hormone-induced breast cancer and metastatic spread to bone. In this review, we will focus on the various RANK/RANKL functions ranging from bone physiology, immune regulation, and initiation of breast cancer.     

From symbolism to information? – Decoding the gene code

‘Information’ and ‘code’ originated as technical terms within linguistics and information theory but are now widely used in genetics and developmental biology. Against this background, it is examined if coded information distinguishes genes from other information carriers, i.e., whether there are genetic words or sentences by virtue of the genetic code, and, if so, whether they have any semantic content. It is concluded that there is no genetic language with semantic content, but that the genetic code still enables unique language-like modes of transmission and interpretation of causal information.     

Thelazia callipaeda in Slovakia – From sporadic cases to endemic areas

Spirurid nematode Thelazia callipaeda, transmitted by the fruit fly Phortica variegata, is a causative agent of an ocular parasitic disease called also canine thelaziosis. Dogs, cats, and wild canids are considered the primary definitive hosts for the parasite, but humans may also serve as aberrant definitive hosts. For long decades the geographic range of T. callipaeda was strictly limited to the territory of Asia, but after the year 2000, the parasite began to spread rapidly through Europe. The first autochthonous infections of dogs and foxes in Slovakia were recorded in 2016. In the present study, the results of a whole-area surveillance for canine thelaziosis are reported. Altogether, 142 cases of infection caused by T. callipaeda were diagnosed by veterinarians in dogs between 2016 and the first quarter of 2021, and two cases of feline thelaziosis were recorded. The majority of the dogs showed mild ocular signs manifested by conjunctivitis; 8.5% of them suffered from more serious mucopurulent discharge, and in two dogs corneal ulceration was recorded. The screening revealed increasing trends in the occurrence of canine thelaziosis from both a temporal and spatial point of view and unambiguously confirms the endemic status of T. callipaeda in Slovakia with the prospect of its further expansion.     

SNP-PHAGE – High throughput SNP discovery pipeline

Background  

Single nucleotide polymorphisms (SNPs) as defined here are single base sequence changes or short insertion/deletions between or within individuals of a given species. As a result of their abundance and the availability of high throughput analysis technologies SNP markers have begun to replace other traditional markers such as restriction fragment length polymorphisms (RFLPs), amplified fragment length polymorphisms (AFLPs) and simple sequence repeats (SSRs or microsatellite) markers for fine mapping and association studies in several species. For SNP discovery from chromatogram data, several bioinformatics programs have to be combined to generate an analysis pipeline. Results have to be stored in a relational database to facilitate interrogation through queries or to generate data for further analyses such as determination of linkage disequilibrium and identification of common haplotypes. Although these tasks are routinely performed by several groups, an integrated open source SNP discovery pipeline that can be easily adapted by new groups interested in SNP marker development is currently unavailable.     

The South China sea: From conflict to cooperation?

This article provides a comprehensive review of the latest developments with respect to the Spratly Islands disputes in the South China Sea. By studying the national policies behind the evolution of these events it examines in particular some of their implications on regional relations and the future of the South China Sea, with special emphasis on China's policy toward the issue.     

From libraries to candidate: the discovery of new ultra long-acting dibasic β₂-adrenoceptor agonists

Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan?) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.     

The gastrointestinal tract of Adélie penguins – morphology and function

The aim of this study was to provide data on the morphology of the gastrointestinal tract of Adélie penguins (Pygoscelis adeliae). It was found to consist of a long oesophagus, a two-chambered stomach, a small intestine measuring only 5.22body length, two rudimentary caeca and a short colon, typical of carnivorous birds. The stomach comprised a glandular proventriculus and a muscular gizzard that frequently contained grit. An acidic pH was recorded in both chambers. Ultrastructural studies of the small intestinal mucosal membrane revealed epithelial cells with elongated, irregular microvilli and high affinity for toluidine blue, absorptive intestinal epithelial cells and goblet cells. Numerous large lymphocyte-like cells were observed close to the brush border of the epithelium, and empty spaces on the epithelial surface reflected normal cell loss in the small intestine. The rudimentary caeca and colon provide relatively little volume and time for symbiotic bacteria to aid the digestion of crustacean chitin.