Agouti: from mouse to man, from skin to fat

The agouti protein regulates pigmentation in the mouse hair follicle producing a black hair with a subapical yellow band. Its effect on pigmentation is achieved by antagonizing the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (Mc1r), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). Dominant mutations in the non-coding region of mouse agouti cause yellow coat colour and ectopic expression also results in obesity, type 11 diabetes, increased somatic growth and tumourigenesis. At least some of these pleiotropic effects can be explained by antagonism of other members of the melanocortin receptor family by agouti protein. The yellow coat colour is the result of agouti chronically antagonizing the binding of alpha-MSH to Mc1r and the obese phenotype results from agouti protein antagonizing the binding of alpha-MSH to Mc3r and/or Mc4r. Despite the existence of a highly homologous agouti protein in humans, agouti signal protein (ASIP), its role has yet to be defined. However it is known that human ASIP is expressed at highest levels in adipose tissue where it may antagonize one of the melanocortin receptors. The conserved nature of the agouti protein combined with the diverse phenotypic effects of agouti mutations in mouse and the different expression patterns of human and mouse agouti, suggest ASIP may play a role in human energy homeostasis and possibly human pigmentation.     

Social Darwinism: from reality to myth and from myth to reality

Considering the variety of contradictory definitions which have been attributed to the term in the course of more than a century, one may be tempted to admit that 'Social Darwinism' can be reduced to a social myth. But it seems nevertheless necessary to answer the question: what has been called 'Social Darwinism' for more than one century and why was the expression used in a negative way to express contradictory opinions which sometimes have nothing to do with Darwin's theory. What we still call 'Social Darwinism' is the result of a misunderstanding: the theories expressed under that phrase have little to do with the Darwinian concepts of natural selection or descent with modification. They have their origin in a pre-darwinian conception of the struggle for existence, which Darwin used in a metaphorical sense. This confusion will then appear to refer clearly to the relationship we establish between biology and society, whether biological laws are directly prolonged in society, or more or less intermingle in a close network. The issue of the definition of Social Darwinism depends obviously on the possible answers to this question, and so does the issue of redefining Darwinism at large.     

Human brain reflexes: from stimulus to recognition and from decision to action

The paper presents a survey of the data, obtained in laboratories, directed by the author, on the problem of the brain bases of psychics. Phenomena of perception, thinking and taking decision about behavioural response correspond to the afferent, central and efferent parts of the reflex arch. Psychic function arises on the basis of complex organization and integration of the processes in the brain. It is shown that sensation is based on the synthesis in the cortical projection area of the information on physical and signal properties of the stimulus. By means of the method developed in the laboratory, of mapping of intracortical interaction the participation is studied of different cortical zones in the process of mental creation of visual image. The process of taking decision is studied by a new method: "reaction choice potential" recorded in the case of decision, about the character of reaction to signal controlled by consciousness.     

Coenzyme A precursors flow from mother to zygote and from microbiome to host

1. Download : Download high-res image (182KB)
2. Download : Download full-size image

     

Profilins Purified from Higher Plants Bind to Actin from Cardiac Muscle and to Actin from a Green Alga

Profilins purified from Zea mays transiently enhance the viscosityof polymerizing cardiac actin at ratios (profilin : actin) <1,but lower the viscosity at higher ratios. Specific binding ofactin from the alga Chara corallina to higher plant profilinssuggests strict conservation of interaction between both proteinsin plants. (Received November 2, 1993; Accepted April 27, 1994)     

Messages from the morgue to rheumatology: from Chagas disease to giant cell arteritis

Autopsy rates have fallen from over 50% to less than 10% in recent decades. The drastic decline creates uncertainty regarding causes of death and has negative effects for research, training, and patient safety, despite advances in imaging and laboratory testing. Rheumatology is as much at a loss as other specialties. Examples are given of important missed diagnoses revealed only at autopsy.When I was a medical school student in the 1950s and a resident and junior staff member in the 1960s and 1970s, regular visits to the morgue were an indispensable part of our workday routine. No first-class teaching hospital could operate without an adequate post-mortem service. The contact between clinicians and pathologists in the morgue was an essential part of ultimate quality control and teaching and could stimulate collaborative research. In the city of Malmö, where the autopsy rate exceeded 80% of the population in the 1970s, it is now less than 10%. When I asked a resident when he last had been to a morgue, he answered ‘I was there once when still a medical student’. Do the improved diagnostic instruments available today fully compensate for the lack of direct information given by careful autopsies, or are we missing valuable information by neglecting routine autopsy? All evidence indicates that we are indeed missing important information.In the 1970s, a 65-year-old man received treatment for systemic sclerosis on the basis of skin thickening, dysphagia, constipation with abdominal pain, and cardiomegaly. Two days before Christmas Eve he died of heart failure. The next day, the professor in the morgue greeted us with a big smile: ‘Today it is Christmas even here. I have today sectioned my first case of Chagas disease’. The patient, a teacher, had spent time in Colombia, a fact the clinicians had paid little attention to. The physician in charge of the patient did research in scleroderma and learned a lesson for life.Professor Kuntal Chakravarty, of Romford, UK, recently told me of a 36-year-old woman with a 5-year history of scleroderma who was admitted with acute abdominal pain, vomiting, and fever. X-rays and ultrasound did not reveal a cause. Owing to her scleroderma, the surgeons were reluctant to perform laparotomy, and she was treated with parenteral antibiotics and intravenous fluid. Her condition improved initially but later deteriorated and she died. The clinical diagnosis was peritonitis and ruptured intestine. The consulting rheumatologist (KC) and the family insisted on an autopsy, which unexpectedly showed uncomplicated volvulus.In 1975, we published an article on cause of death in 104 patients with rheumatoid arthritis (RA) based on routine post-mortem examination of patients during 5 years in a chronic care hospital in Malmö [1]. Cervical spine compression was identified as the cause of death in 11 patients. Only two of the cases had been diagnosed before death, although all patients had been hospitalized for months or years [1]. Although cervical spine instability is now rare, it still occurs and may be prevalent in communities with undeveloped health systems [2].Very high autopsy rates generated accurate prevalence studies of atherosclerosis [3], thromboembolism [4] and cancer [5,6]. In 1969, when the autopsy rate was 65%, Görel Östberg examined all 1,097 (!) temporal arteries from patients dying in 1 year in the city of Malmö, which had 250,000 inhabitants. The prevalence according to the literature was 2 out of 100,000, but Östberg identified not fewer than 16 out of 1,000 patients with a male/female ratio of 6/10. Only two of the patients had received a clinical diagnosis of temporal arteritis (retrospectively), and only a couple had suggestive symptoms [7]. Even more interesting is her systematic study of large vessel involvement in polymyalgia rheumatic and temporal arteritis, showing their overlap and coexisting polyarteritis nodosa and Takayasu’s disease [8]. This work has recently been fully acknowledged and extended by Gary S Hoffman and the US Vasculitis Clinical Research Consortium [9].In Finland, rheumatologists have published a number of articles illustrating substantial discrepancies between clinical and autopsy-based causes of death. In 36% of 371 autopsied patients, significant infections were identified, only half of which had been diagnosed in vivo[10]. Amyloidosis was the cause of death in 9.5% of patients between 1950 and 1991; of these cases, 35% had not been diagnosed in vivo[11]. Coronary heart disease showed an increasing prevalence in the same time period in the RA patients in contrast to autopsied non-RA patients and were likewise often not detected before death [12].In the US, the autopsy rate dropped from above 70% in the 1960s to 20% in 2005 at the Mayo Clinic and the Brigham and Women’s Hospital. The overall rate in the US is now 4.3% in non-forensic cases [13]. Although advances in diagnostic tools have improved accuracy of clinical diagnostics, 8% of major errors were found in a systematic review of 53 publications [14]. Post-mortem imaging has been investigated as an alternative to autopsy [15]. An ambitions blinded comparison between computed tomography (CT), magnetic resonance imaging (MRI), and autopsy of 182 cases reported to the coroner between 2006 and 2008 showed that CT was as accurate as the clinical diagnosis but that nevertheless causes of sudden death were often missed. MRI was less accurate than CT [16]. Even in the context of experimental medicine, the trend is the same. In the Autologous Stem Cell Transplantation International Scleroderma trial of stem cell transplantation versus cyclophosphamide in diffuse systemic sclerosis, autopsy was performed in 7 out of 44 cases (Jaap van Laar, of Newcastle, UK, and Kamran Naraghi, of Middleborough, UK).

Conclusions

The decline in autopsy rates has several causes: diagnostic overconfidence, physician reluctance to pursue consent for autopsy, lack of regulatory requirements, public resistance, and budgetary constraints. Part of the problem is that doctors are short on time and motivating the family to agree to autopsy requires tact, time, and dedication. Reluctance to embark on the additional paper work may also contribute. Autopsy remains the gold standard for determining the cause of death [13], and although revitalizing it seems unrealistic, I feel a need to alert younger generations what they are missing, in rheumatology as in other specialties.

Box 1. About Frank Wollheim

Frank Wollheim is Emeritus Professor at the Department of Rheumatology, University of Lund. He was its chairman from 1982 to 1998 and started its programs in scleroderma, systemic lupus erythematosus, early rheumatoid arthritis, and biomarkers of arthritis. He trained in internal medicine with Jan Waldenström in Malmö and rheumatology with Ralph C Williams in Minneapolis before starting the first rheumatology unit in Malmö in 1972. He has served as Secretary General and board member of Osteoarthritis Research Society International and is a master member of the American College of Radiology.

Abbreviations

CT: Computed tomography; MRI: Magnetic resonance imaging; RA: Rheumatoid arthritis

Competing interests

The author declares that he has no competing interests.     

Novel transaminases from thermophiles: from discovery to application

Transaminases (TAs) are promising biocatalysts for chiral amine synthesis; however, only few thermophilic TAs have been described to date. In this work, a genome mining approach was taken to seek novel TAs from nine thermophilic microorganisms. TA sequences were identified from their respective genome sequences and their Pfam were predicted confirming that TAs class I–II are the most abundant (50%), followed by class III (26%), V (16%), IV (8%) and VI (1%). The percentage of open reading frames (ORFs) that are TAs ranges from 0.689% in Thermococcus litoralis to 0.424% in Sulfolobus solfataricus. A total of 94 putative TAs were successfully cloned and expressed into E. coli, showing mostly good expression levels when using a chemical chaperone media containing d -sorbitol. Kinetic and end-point colorimetric assays with different amino donors–acceptors confirmed TAs activity allowing for initial exploration of the substrate scope. Stereoselective and non-stereoselective serine-TAs were selected for the synthesis of hydroxypyruvate (HPA). Low HPA reaction yields were observed with four non-stereoselective serine-TAs, whilst two stereoselective serine-TAs showed significantly higher yields. Coupling serine-TA reactions to a transketolase to yield l -erythrulose (Ery) substantially increased serine conversion into HPA. Combining both stereoselective serine-TAs and transketolase using the inexpensive racemic D/L-serine led to high Ery yield (82%). Thermal characterization of stereoselective serine-TAs confirmed they have excellent thermostability up to 60°C and high optimum temperatures.     

Combining bio- and chemo-catalysis: from enzymes to cells, from petroleum to biomass

In the future, biomass will continue to emerge as a viable source of chemicals. The development of new industries that utilize bio-renewables provides opportunities for innovation. For example, bio- and chemo-catalysts can be combined in 'one pot' to prepare chemicals of commercial value. This has been demonstrated using isolated enzymes and whole cells for a variety of chemical transformations. The one-pot approach has been successfully adopted to convert chemicals derived from biomass, and, in our opinion, it has an important role to play in the design of a more sustainable chemical industry. To implement new one-pot bio- and chemo-catalytic processes, issues of incompatibility must be overcome; the strategies for which are discussed in this opinion article.     

Mapping from GenBank to MEDLINE

GenBank has been based largely on literature that provides nucleic acid sequences. To find additional literature that is relevant to a given sequence, a search of MEDLINE can prove helpful. This paper documents some of the similarities between GenBank and MEDLINE that facilitate retrieval of documents from MEDLINE. In particular, techniques and examples are presented which take GenBank information and lead to MEDLINE information that supplements the GenBank information.     

Mannosyltransfer from GDP-mannose to oligosaccharide-lipids

Rabbit liver microsomes catalyzed mannosyltransfer from GDP-mannose to oligosaccharide-lipids isolated from porcine liver. The transfer occurred in the presence of 10 mM EDTA, a condition under which the formation of dolichol-P-mannose and other chloroform soluble mannosyl-lipids was almost completely inhibited, indicating that the mannosyl-oligosaccharide linkage was formed by a direct transfer of mannose from the nucleotide sugar. Virtually all of the mannose incorporated into the oligosaccharides was released by α-mannosidase, demonstrating the formation of an α-mannosyl-linkage in the oligosaccharide-lipid product. An enzyme catalyzing the divalent cation independent transfer of mannose from GDP-mannose to exogenous oligosaccharide-lipids was solubilized from rabbit liver microsomes and purified over 10 fold.