Ubiquitin system

The complexities of the ubiquitin system are fully described in Nature 2009 vol 458 pages 422 to 467.


Page 422 Hochstrasser Origin and function of ubiquitin-like proteins.
The function of proteins can be modulated through a wide array of post-translational modifications. One such modification in eukaryotic cells is ubiquitylation - the covalent attachment of a small, highly conserved protein called ubiquitin to other proteins, either
as a monomer or in polymeric chains. Increasing evidence indicates that this system has evolved from the sulphurtransferase system that operates in prokaryotes. Furthermore, protein-sequence comparison and structural analysis indicate that bacteria contain many ubiquitin-like proteins.
Page 430 Bhoj &. Chen Ubiquitylation in innate and adaptive immunity
By attaching to a substrate through different linkages, ubiquitin can either target it to the proteasome for destruction or regulate its activity and localization. Ubiquitylation is extensively used in the initiation, amplification and termination of the immune response. One of the best studied examples is the activation of the nuclear factor-xb signalling pathway, which is important in both innate and adaptive immunity. Recent research has revealed the importance of the ubiquitin system in developing immune tolerance and thereby preventing autoimmune diseases.
Page 438 Hoeller & Dikic Targeting the ubiquitin system in cancer therapy .
Many of the cellular processes regulated by ubiquitylation - such as cell-cycle progression, apoptosis, receptor downregulation and gene transcription - are relevant to tumorigenesis. Deregulation of the ubiquitin system is implicated in the initiation and progression of various cancers. A knowledge of which components of the system are affected in what cancer could not only aid in the development of new anticancer agents, but also be relevant to diagnosis. Efforts are already underway to target components of the ubiquitin system that are affected in cancer, with stories of both success and failure abounding.
Page 445. Raiborg & Stenmark The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins .
Membrane proteins destined for degradation are delivered to lysosomes by way of multivesicular endosomes (MVEs). Ubiquitylation ensures that these proteins are sorted into vesicles within the endosomal lumen. The endosomal sorting complex required for transport (ESCRT) performs three main functions. It recognizes ubiquitylated cargo, deforms the endosomal membrane and catalyses the final abscission of the invaginations to form intraluminal vesicles that contain the cargo. The resultant MVE eventually fuses with Iysosomes, where cargo is degraded. In addition to MVE biogenesis, the E5CRT machinery is involved in diverse processes such as viral budding, cytokinesis and autophagy and protects against disorders such as neurodegeneration and cancer.
Page 453 Hirsch, Gauss, Horn, Neuber & Sommer The ubiquitylation machinery of the endoplasmic reticulum
Newly synthesized proteins are transported to the endoplasmic reticulum (ER), where an array of molecular chaperones guide and assist the proteins in their maturation. Proteins that do not reach their native conformation owing to mutations or to errors in transcription or translation, as well as mature proteins that have been damaged by environmental conditions such as highenergy radiation, clog up the ER, impairing its efficiency. The ER therefore uses a quality-control system, consisting of glycan codes and the ubiquitin system, to identify the defective proteins and transport them out of the organelle to the cytoplasm for destruction.
Page 461 Bergink & Jentsch Principles of ubiquitin and SUMO modifications in DNA repair .
Within the cell, ubiquitylation, and the related process SUMOylation, affect all major DNA-repair pathways, damage-avoidance mechanisms and checkpoint responses in one way or another.
For instance, ubiquitin and SUMO molecules can tag for degradation either stalled enzymes or proteins that have completed their DNA-repair function. As maintenance of genomic stability is essential for health, dysfunction of the ubiquitin and SUMO systems has been associated with a range of diseases linked to inefficient DNA repair, including cancer and Fanconi anaemia.

flavone metabolism

This paper by Brett and colleagues is such a good study of flavone metabolism.
Oranges are rich sources of flavonoids that are bioactive and may protect against age-related diseases. The absorption of orange flavanones may be affected by factors such as processing and subject anthropometric variables, and the bioactivity of the absorbed phytochemicals depends on how they are metabolised during absorption.
In a randomised cross-over study, twenty subjects consumed a single portion of orange fruit (150 g) or juice (300 g) that contained the flavanones narirutin and hesperidin, and an additional 109 subjects across a broad age range (18-80 years) consumed the juice.
The natural forms of the flavones are glycosides. In different flavones hesperitin, naringenin and eriodictyol vary in their hyeroxyl and methoxyl substiutions in the flavin A- and B rings. Oranges are rich in flavones.
Flavanone metabolites were measured in regularly collected samples of plasma and urine. After consumption of fruit or juice, flavanone conjugates, but not the aglycones, were detected in plasma and urine. The flavanone conjugates were shown to include the 7- and 4'-O-monoglucuronides of naringenin, the 7- and 3'-O-monoglucuronides of hesperetin, two hesperetin diglucuronides and a hesperetin sulfo-glucuronide, but no aglycones or rutinosides. Analysis of the plasma pharmacokinetic and urinary excretion data on a dose-adjusted basis indicated no difference in absorption or excretion of either flavanone between the fruit and juice matrices. In the extended urinary excretion dataset the individual variation was very large (range 0-59 % urinary yield). There was a small but significant (P< 0·05) decrease in the excretion of hesperetin (but not naringenin) with increasing age (P<0·05), but the effects of sex, BMI and contraceptive pill use were shown not to be associated with the variation in flavanone excretion.


Gary M. Brett et al 2009 Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion British J Nutriiton vol 101 pp 661-675

nutrition in life and later life

Burdge and colleagues discuss the substantial evidence which shows that constraints in the early life environment are an important determinant of risk of metabolic disease in adult life.. There is emerging evidence that higher birth weight, which reflects a more abundant prenatal environment, is associated with increased cancer, in particular breast cancer and childhood leukaemia. Using specific examples from epidemiology and experimental studies, this review discusses the hypothesis that increased susceptibility to CVD, metabolic disease and cancer have a common origin in developmental induced in the developing fetus by aspects of the intra-uterine environment including nutrition which involve stable changes to the genetic regulation of specific genes. However, the induction of specific disease risk is dependent upon the nature of the environmental challenge interactions between the susceptibility set by the altered epigenome and the environment throughout the life course.
Cancer is the result of derangement of cellular processes which control cell division and apoptosis. While gene mutation has a role in the aetiology of cancer, there is increasing evidence which shows that epigenetic processes such as DNA methylation and covalent modification to histones are also involved. Such epigenetic changges represent potential for altered gene activity and hence cellular dysregulation. These may only be manifest when the gene is exposed to an appropriate environmental
signal which is enhanced or diminished as a consequence of epigenetic change compared to normal cells.
The early life environment has been shown to be an important factor in determining risk for some types of cancer. Measures of growth in early life show statistical associations with risk of specific cancers. In this context, there appear to be parallels between causal processes in cancer with metabolic disease and CVD in which the early life environment and epigenetic processes lead to a susceptibility which increases the risk to later specific environmental exposures.
Burdge et al 2009 Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale . Brit J Nutrition vol 101 p 619-30

juice and inflammation

Inflammation and endothelial activation are associated with an increased risk of vascular disease. Epidemiological evidence suggests an association between levels of markers of inflammation or endothelial activation and the intake of fruit. Vitamin E, a fat-soluble antioxidant, has anti-inflammatory properties. Dalgard and colleagues performed a randomised 2 X 2 factorial, crossover trial to determine the effect of orange and blackcurrant juice (500 ml/d) and vitamin E (15 mg RRR-a-tocopherol/d) supplementation on markers of inflammation and endothelial activation in forty-eight patients with peripheral arterial disease. Patients were randomly allocated to two dietary supplements from the four possible combinations of juice and vitamin E: juice + vitamin E; juice + placebo; reference beverage (sugar drink) + vitamin E; and reference beverage + placebo. The supplementations were given for 28 d, separated by a 4-week wash-out period. Analysis of main effects showed that juice decreased C-reactive protein (CRP) by 11 % and fibrinogen by 3 % while the reference drink increased CRP by 13 % and fibrinogen by 2 % (P< 0·008 and P< 0·002, respectively). No significant differences were measured for IL-6 and the endothelial activation markers von Willebrand factor, tissue-plasminogen activator and plasmin activator inhibitor-I. Vitamin E supplementation had no significant effects on the various markers. We observed no significant interaction between juice and vitamin E. In this study, orange and blackcurrant juice reduced markers of inflammation, but not markers of endothelial activation, in patients with peripheral arterial disease, relative to sugar drinks.
Dalgard et al 2009 Supplementation with orange and blackcurrant juice, but not vitamin E, improves inflammatory markers in patients with peripheral arterial disease British Journal of Nutrition (2009), 101, 263-269


Fruit juice: Vitamin E: Inflammation: Oxidative stress: Peripheral arterial disease

lipaemia and exercise

A single bout of prolonged, moderate-intensity endurance exercise lowers fasting and postprandial triacylglycerolaemia concentrations the next day. However, the triacylglycerolaemia -lowering effect of exercise is dose-dependent and does not manifest after light exercise of low energy input.. Maraki and colleagues have described a study examining if adding mild energy intake restriction to such exercise, in order to augment total energy deficit, would potentiate the hypotriacylglycerolaemic effect.
Eight healthy, sedentary,young , slim under 30 years of age premenopausal women , BMl 21·8 (SEM 0·9) kg/m2) performed two oral fat tolerance tests in the morning on two different occasions: once after a single bout of light exercise (100 min at 30 % of peak oxygen consumption; net energy expenditure 1·04 MJ coupled with mild energy intake restriction (1·39 (SEM 0·22) MJ) on the preceding day, and once after resting coupled with isoenergetic feeding on the preceding day (control). Fasting plasma triacylglycerols, in the triacylglycerol-rich lipoproteins (TRL-TAG) and serum insulin concentrations were 18,34 and 30% lower, respectively, after exercise plus diet compared with the control trial (P<0·05). Postprandial concentrations of plasma TAG and TRL-TAG were 19 and 27 % lower after exercise plus diet compared with the control condition (P< 0·01), whereas postprandial insulin concentrations were not different. They concluded that a combination of light exercise along with mild hypoenergetic diet might be a practical and feasible intervention to attenuate fasting and postprandial triacylglycerolaemia, especially for people who cannot exercise for prolonged periods of time at moderate-to-high intensities, such as many sedentary individuals.
It would be of interest to see if the same effect was possible in well built mature ladies and men.
Maraki et al 2009 Exercise of low energy expenditure along with mild energy intake restriction acutely reduces fasting and postprandial triacylglycerolaemia in young women. Brit J Nutrition vol 101, 408-416

body clocks

This is complex thinking but indicates how easy it is to be rite about global warming and to think the answers are easy. The absorption of carbon by oceans is an important feature of the carbon chain and this is an important article by Gruber in Nature 11th March 2009
Recent studies have suggested that the carbon sink in the North Atlantic f Ocean has decreased in recent decades, possibly as a result of long-term climate change. Writing in Global Biogeochemical Cycles, Thomas et al. propose that this interpretation needs to be viewed with " great caution. From their modelling work, they argue that the observed trends instead reflect fluctuations over decades and are a response to climate variability in the North Atlantic region.
The oceanic sink, which has removed about 30% of the global anthropogenic emissions over the past 250 years or so, might be stalling. Some of the best observational evidence comes from the North Atlantic Ocean, where long-term measurements of the surface ocean's partial pressure of CO2 (PC02) indicate that its carbon uptake from the atmosphere has decreased in recent decades, perhaps owing to climate change. Thomas et al. challenge this interpretation.
The North Atlantic is the largest ocean sink for atmospheric CO2 in the Northern Hemisphere, with half of the flux in the North Atlantic being driven by the uptake of man made CO2 . The detection of long-term changes in this sink is challenging, however, because the sink varies substantially from year to year. That variation is largely associated with the North Atlantic Oscillation (NAO), which is the dominant mode of climate variability in this region.
The NAO is a large-scale seesaw in atmospheric mass between a subtropical high pressure system, typically near the Azores, and a subpolar low near Iceland. A positive phase of the NAO - that is, a stronger pressure gradient between these two systems - is associated with more and stronger winter storms crossing the North Atlantic on a more northerly route, causing major anomalies in sea surface temperature, currents and convective activity throughout the North Atlantic
In a positive phase, a stronger Azores high and stronger Icelandic low produce more and stronger winter storms on a more northerly track. As a consequence, the subtropical gyre extends northwards, and the North Atlantic Current accelerates, transporting increased amounts of warm, saline waters with low carbon concentrations northeastwards, This causes an intensified sink (minus sign) in the eastern subpolar North Atlantic, because these waters have the potential to take up a large amount of CO, from the atmosphere when they are cooled along their northward journey. At the same time, the Labrador Current intensifies, bringing fresher, colder waters with high carbon concentrations from the
Arctic into the subpolar gyre, creating a diminished sink (plus sign) near the coast of Canada. In the subtropical gyre, warm conditions and reduced convective activity also lead to reduced carbon uptakes.
Grubwer 2009 Fickle trends in the ocean Nature vol 458 pp 155-6

ocean carbon sinks

This is complex thinking but indicates how easy it is to be rite about global warming and to think the answers are easy. The absorption of carbon by oceans is an important feature of the carbon chain and this is an important article by Gruber in Nature 11th March 2009
Recent studies have suggested that the carbon sink in the North Atlantic f Ocean has decreased in recent decades, possibly as a result of long-term climate change. Writing in Global Biogeochemical Cycles, Thomas et al. propose that this interpretation needs to be viewed with " great caution. From their modelling work, they argue that the observed trends instead reflect fluctuations over decades and are a response to climate variability in the North Atlantic region.
The oceanic sink, which has removed about 30% of the global anthropogenic emissions over the past 250 years or so, might be stalling. Some of the best observational evidence comes from the North Atlantic Ocean, where long-term measurements of the surface ocean's partial pressure of CO2 (PC02) indicate that its carbon uptake from the atmosphere has decreased in recent decades, perhaps owing to climate change. Thomas et al. challenge this interpretation.
The North Atlantic is the largest ocean sink for atmospheric CO2 in the Northern Hemisphere, with half of the flux in the North Atlantic being driven by the uptake of man made CO2 . The detection of long-term changes in this sink is challenging, however, because the sink varies substantially from year to year. That variation is largely associated with the North Atlantic Oscillation (NAO), which is the dominant mode of climate variability in this region.
The NAO is a large-scale seesaw in atmospheric mass between a subtropical high pressure system, typically near the Azores, and a subpolar low near Iceland. A positive phase of the NAO - that is, a stronger pressure gradient between these two systems - is associated with more and stronger winter storms crossing the North Atlantic on a more northerly route, causing major anomalies in sea surface temperature, currents and convective activity throughout the North Atlantic
In a positive phase, a stronger Azores high and stronger Icelandic low produce more and stronger winter storms on a more northerly track. As a consequence, the subtropical gyre extends northwards, and the North Atlantic Current accelerates, transporting increased amounts of warm, saline waters with low carbon concentrations northeastwards, This causes an intensified sink (minus sign) in the eastern subpolar North Atlantic, because these waters have the potential to take up a large amount of CO, from the atmosphere when they are cooled along their northward journey. At the same time, the Labrador Current intensifies, bringing fresher, colder waters with high carbon concentrations from the
Arctic into the subpolar gyre, creating a diminished sink (plus sign) near the coast of Canada. In the subtropical gyre, warm conditions and reduced convective activity also lead to reduced carbon uptakes.
Grubwer 2009 Fickle trends in the ocean Nature vol 458 pp 155-6

malnutrition and farming

A commentary in nature 12th March 2009 discusses ways of combating the starvation or sub clinical malnutrition, which wrecks nearly 1000 million people in the world.
Instead of food aid that farming be encouraged or that food be bought locally and given. This is recommendation of the Food and Agriculture Organization of the United Nations.
The relative costs are enormous
To buy ship and distribute a tone of US maize in Africa costs $US 812
To buy a tonne of maize locally and to distribute $US 320
To give farmers fertilizer, seed and support to grow an extra tonne of maize $US 135.
This is such a good idea beset with problems.
On the plus side
This gives work and inexpensive food to local communities.
On the negative side.
Is land available?.
US farmers will be coming to rely on this food distribution for their own sales at a bad time for Farming
Drought is a real problem in Africa so irrigation is a possible requirement
Disease amongst these malnourished communities is endemic.
But these are problems and challenges to be overcome and the real joy of this idea is it gives a multi facetted hoe to communities.
Sanchez 2009 A smarter way to combat hunger Nature vol 458 p 148

avoiding strokes

The BMJ of 14th March2009 has two articles on the avoidance of stokes.
The first by Myint et al show that four health variables smoking, physical activity, alcohol intake and frit and vegetable intake ( measured by vitamin C serum concentration ) produce a substantial reduction in risk of a stroke.
Smoking is shown is great detail by Gruer et al to have a profound effect on survival regardless of ender, social status or any other parameter.
Myint et al 2009 Combined effect of health behaviours and risk of first stroke in 20040 men and women over 11 years follow-up in a Norfolk cohort of European Prospective Investigation of Cancer ( EPIC) : prospective study BMJ vol 338 pp 639-642
Gruer et al 2009 Effect of tobacco smoking on survival of men and women by social position : a 28 year cohort BMJ vol 338 pp 643
Giles 2009 Risk of stroke and lifestyle BMJ vol 3388 pp 610-11

Gene silencing and control

This does not appear to be of any relevance to nutrition. I think this kind of discovery is central to the future of our science. Nutrition may play a central role in these process of control. Maybe by the usual chemicals in amino acids, proteins carbohydrates and lipids or less directly with plant secondary metbaolitres.
The discovery of RNA interference (RNAi) began a revolution in RNA biology. Previously 'hidden' layers of regulation of gene expression, families of small RNAs (consisting of 20-30 nucleotides) are involved in gene silencing. A diverse set of gene- regulatory mechanisms were found to use key steps in the RNAi process, including mechanisms that silence endogenous genes and mechanisms that restrain the expression of parasitic and pathogenic invaders such as transposons and viruses.
The basic RNAi process can be divided into three steps.
1. a long double-stranded RNA (dsRNA) that is expressed in, or introduced into, the cell (for example, as a result of the base-pairing of sense and antisense transcripts or the formation of stem-loop structures) is processed into small RNA duplexes by a ribonuclease III (RNaseIII) enzyme known as Dicer.
2. These duplexes are unwound, and one strand is preferentially loaded into a protein complex known as the RNA-induced silencing complex (RISC).
3. This complex effectively searches the transcriptome and finds potential target RNAs. The loaded single-stranded RNA (ssRNA), called the guide strand, then directs an endonuclease that is present in the RiSe (sometimes called the 'slicer' and now known to be an Argonaute protein to cleave messenger RNAs that contain sequence homologous to the ssRNA, over many rounds. In this way, the guide strand determines the sequence specificity of the RNAi response.
In different organisms, the RNAi pathways involve different proteins and mechanisms, but they operate by similar strategies. In all organisms that have been studied, RNAi involves two main components: small RNAs, which determine the specificity of the response; and Argonaute proteins, which carry out the repression. Depending on both the nature of the Argonaute in the RISC and the degree of complementarity between the small RNA and the target sequence in the mRNA, the association of the RISC with target mRNAs has been shown to have different outcomes: it can control protein synthesis and mRNA stability, maintain genome integrity or produce a specific set of small RNAs.
RNAi systems in different organisms have been refined in many ways, and such modifications include built-in molecular 'rulers' that define the size of small RNAs, structures that determine which strand of a small RNA is selected, mechanisms that direct further rounds of small RNA amplification, or safeguards against off-target (unrestricted and unrelated) silencing.
Siomi and Siomi 2009 On the road to reading the RNA-interference code Nature vol 457 pp 396-433
Jinek and Doudna 2009 A three dimensional view of the molecular machinery of RNA interference vol 457 pp 405-412
Moazed 2009 Small RNAs in transcriptional gene silencing and genome defence Nature vol 457 pp 413-420
Cullen 2009 Viral and cellular messenger RNA targets of viral microRNAs Nature vol 457 pp 420-425
Castanotto and Ross 2009 The promises and pitfallsof RNA-interference based therapeutics vol 457 426-433

ATP complexes

Enzyme proteins frequently combine to form multimeric complexes that allow individual subunits to coordinate their activities and so perform more difficult tasks than they could alone. An example of such a complex is the ring ATPases in which several subunits form circular complexes consisting of identical (homomeric) or non-identical (heteromeric) subunits. These enzyme complexes use energy released from the hydrolysis of ATP molecules to perform diverse cellular functions, such as DNA translocation, protein degradation and ion transport.
Subunits of the various ring ATPases can coordinate their activities in different ways. For instance, the three heterodimers of the Fl- ATPase act sequentially, each binding an ATP molecule and hydrolysing it in order. By contrast, subunits of the L Tag helicase of simian virus 40 seem to act in concert, all six of them simultaneously binding then hydrolysing ATP molecules. Subunits of the unfoldase enzyme ClpX, however, are thought to act randomly, each one hydrolysing ATP independently, with their activities probably being coordinated by the geometry of the complex.
Abbondanzieri and Zhuang 2009 Concealed enzyme co-coordination Nature vol 457 pp 392 - 3

predictors of growth in children.

I had always believed that a babies height at 2 ½ years was a good predictor of the adult age Giante et al have investigateed socioeconomic, gestational and early life exposures as potential determinants of total height, leg and trunk length.
Male subjects from the 1982 Pelotas Birth Cohort Study were examined in 1986 at home, and in 2000 when registering at the local army base. The follow-up rate was 79%. Standing and sitting heights were measured on both occasions. Leg length was calculated as the difference between standing and sitting heights. Outcome measures were height, leg and trunk length at 4 and 18 years and growth in this period.
Mean (s.d.) height, trunk length and leg length at 18 years were 173.4 (6.8), 96.0 (3.5) and 77.5 cm (4.5), respectively. The mean (s.d.) change in height from 1986 to 2000 was 75.4 cm (5.2) and for leg and trunk length 35.4 (3.9) and 40.0 cm (2.9), respectively. Only maternal height and birthweight were associated with all three variables of growth. Gestational age showed no associations with growth or attained size.
They concluded that early growth plays a pivotal role in determining attained height and its components. Both biological and socioeconomic variables strongly influence determinants of height, though socioeconomic factors appear to be more important in early growth. Leg and trunk length contribute almost equally to differences in overall height, regardless of the independent variable influencing the difference. Public health strategies designed to improve chronic disease profiles should focus on the early growth period.
Gigante et al (2009); Epidemiology of early and late growth in height, leg and trunk length: findings from a birth cohort of Brazilian males European Journal of Clinical Nutrition 63, 375–381

ageing

This fascinating review Vijg and Campisi discusses question, which may be of interest to all of us, that is whether or not it is possible to extend life expectation. Slowly life expectations is increasing with a target of 120-125 years being seen as possible though at the moment 85 years is a good possibility for many.
Experiments in the nematode show that mutations in single genes can extend life expectation. Most of the 100 or so genes so acting act in evolutionarily conserved pathways that regulate growth, energy metabolism, nutrition, sensing and reproduction eg insulin growth factor (IGF-I ) signalling (IIS) pathway and mitochondrial electron transport chain. Extension of life occurs when activity is reduced, perhaps reducing somatic damage and increasing somatic maintenance.
In mammals mitochondria play a part in signalling apoptosis which has a role in longevity. Also FOXO ( forkhead transcription actors) and silent information regulator ( SIR) protein deacetylases ( sirtuins ). Some FOXO proteins initiate apoptosis which removes dead cells . FOXO proteins also upregulate antioxidant defences.
Many of these pro longevity mutations mimic dietary restriction which increases longevity in many species. Though reduced food intake may act through different mechanisms. It is suggested that small molecular weight molecules would be effective eg polyphenolics such as resveratrol and fisiten, the antifungal agent rapamycin. Glucose metabolism is a key target for current research seeking life extending mechanisms. Vitamin anti-oxidants isolates have had little benefit in this respect.
Maybe optimal conditions for life prolongation are necessary and the results from animals are very species dependent eg dependence upon aerobic respiration.
The process of ageing and why we die is not understood and clearly complex. Also it is useful to differentiate between ageing and disease. Cancer is a case in point which again is species dependent in occurrence. Ageing is influenced as with all biology , by genes and environment.
Vijg and Campisi 2008 Puzzles, promises and a cure for ageing Nature vol 454 pp 1065-71

health benefits of exercise

A really good critique of the essential nature of exercise by Thompson .
Regular and goal-appropriate exercise is critical to improving and maintaining both health and performance. However, the frequency, intensity, duration and type of activities needed to optimise health or achieve successful sports performance will differ considerably depending on an individual's goals and capabilities. Although sport is one of many forms of exercise that can be counted towards daily physical activity, participation in sport is not necessary to meet current physical activity recommendations. The current consensus is that the minimum amount of physical activity needed to improve and maintain good health is 30 min moderate-intensity activity/d on at least 5 d/week. The evidence supporting this consensus is predominantly observational , in that performing regular aerobic (endurancej-type physical activity is associated with reduced morbidity and premature mortality from CVD, CHD, stroke and colorectal cancer. The exact dose needed to improve health and the slope of the dose-response gradient between physical activity and mortality for various diseases are not known, and one major limitation of the existing evidence is the lack of objective measurement of physical activity. Limited evidence indicates that a much higher dose of activity (45-90 min each day on at least 5 d/week) may be needed to prevent overweight and obesity and to avoid weight regain in previously overweight and obese individuals. The role of resistance training and heavy domestic work in reducing morbidity and premature mortality for various diseases is unclear. As most adults do not meet current recommendations there is a critical need for innovative approaches to increase physical activity across large-scale populations.
Thompson 2009 Exercise in improving health v performance. Proceedings Nutrition Society vol 68 pp 29-33.

nutrition in sport

The importance of nutrition in sport is well established and its influence on health, body weight and body composition, substrate availability and ultimately sports performance has widespread acceptance.
A very realistic and excellent review by Gilbert is of importance in this subject.
However, nutritional knowledge, beliefs and practices in sport are extremely variable, with nutritional science often having little bearing on the practices of elite performers. Many aspiring athletes may be prepared to take a risk. Results from scientific studies that are non-significant, but show even a small trend towards benefit, may be viewed as worth trying if they are thought to translate to improved performance in the field. Other athletes, however, may be ill informed or simply lack the opportunity or funding to seek advice from competent sports nutritionists or dieticians. Many organisations delegate nutrition responsibilities to other professionals, often fitness coaches or physiotherapists who have only a basic knowledge of nutrition and may also lack the practitioner skills and expertise to effectively apply theory to practice. Furthermore, sports nutrition is currently a poorly regulated profession, allowing unethical practitioners and individuals without the necessary skills and qualifications to practice, which results in many athletes obtaining information from less-reliable sources, which may also include the media and supplement companies. In practice there are may athletes who are insufficiently advised as to diet.
The review looks at diet and requirements by professional footballers by a hands on nutritionist.
Footballer will have used their glycogen stores within 90 minutes. .A habitual high carbohydrate diet ( 5-7 g/kg is important and an increase on the 2 days before the game. High carbohydrate foods are important on match days. Reliable information for women is not available.
Recovering nutritionally between games in important in reducing fatigue. Carbohydrates are the basis of such diets. The amount varies with age, gender, maturity, fitness status, exercise intensity , duration, recovery period, climate, hydration, size of glycogen stores before and after the games, muscle damage and timing of next exercise.
Protein is not as great as many would believe and at the most in endurance athletes 1.6 g/kg body weight compared to 0.8-1.0 in average people. Female athletes 15 % les than their male equivalents.
Gilbert 2008 Practical aspects of nutrition in performance Proceedings Nutrition Society vol 68 pp 23-28.

alcohol and type 1 diabetes

Little is known about the effect of alcohol when drunk by individuals with type 1 diabetes.
A study by Kerr et al looked at this in 7 males, 3 females with type 1 diabetes of long standing. They ate a standard 600 calorie lunch with 8 units of alcohol for men and 6 for women of wine. They were in excellent glucose control before the meal. There was a control meal with alcohol free drinks.
Whilst glucose, triglycerides, free fatty acids, glycerol, cortisol and growth hormone changes were the same in the two circumstances, there was significant ketosis with alcohol with increased lactate and β-hydroxybutyrate concentrations after alcohol.
The authors conclude that if this could happen in controlled circumstances in normal life , alcohol could have profound effects on ketosis.
This is discussed in a commentary by Song in the same edition of QJM .
Kerrr et al 2009 The influence of liberal alcohol consumption on glucose metabolism in patients with type 1 diabetes: a pilot study. QJM vol 102, 169-174
Song 2009 Alcohol-it’s more than the liver QJM vol 102, 221-222

exercise and fluid loss

Sherreffs has written an important review of the influence of exercise on water and electrolyte loss during sport. Sweat evaporation can be a key thermoregulatory mechanism and it causes a loss of water from all compartments of the body. Hypohydration can also develop with restricted fluid intake or with intake of diuretics. Hypohydration can affect physical and/or mental performance and/or have implications for dietary recommendations. A variety of different types and modes of exercise performance can be influenced by hydration state. Dehydration equivalent to 2 % body mass loss can occur during exercise in a hot environment (3l-32°C) and impairs endurance performance. When the exercise is performed in a temperate environment (20-21°C) a 2 % body mass loss appears to have a lesser and inconsequential effect. In cold environments a body mass loss> 2 % may be tolerable for endurance exercise.
Loss of 3% or more of hypohydration may have effects on intellect and cognitive functions.
There is a less conclusive picture as to the effects of hypohydration on other types of physical performance, including strength and power activities, team sports and the skills component of many sports, and for mental performance. A number of physiological mechanisms are responsible for the effects observed. Fluid consumption can be used to attenuate the development of a water deficit or to correct it. The composition and temperature of a drink and the volume and rate of its consumption can all influence the physiological responses to ingestion and can impact on exercise performance.

Shirreffs 2009 Hydration, fluids and performance Proceedings of the Nutrition Society vol 68 17-22

proteins and trace elemenents

Berks has written a fascinating review of trace elements and their binding to proteins. It has been estimated that a third of all proteins require the help of metal ions to carry out their biological functions'. In most cases, these proteins obtain their metal cofactors directly from their surroundings, and so they need a mechanism to select the correct metal from the pool of metal ions to which they are exposed. A constraint on the selection of di-positive transition-metal ions by proteins is that the strength of the metal-protein interaction which is controlled the type metal ion, rather than by the nature of the binding groups supplied by the protein. This is shown by the Irving- Williams series, in which the affinity of metal ions for binding groups increases in the order manganese, iron, cobalt, zinc, nickel and copper. A protein cannot select one transition-metal ion over another just by changing the metal-binding groups.
Proteins have, therefore, evolved alternative strategies that enable them to bind to specific metals. Binding groups in proteins can be held in fixed positions that match the radius or preferred coordination geometry - the orientation in which a molecule binds a metal - of particular metal ions. Alternatively, specific helper proteins folds, or use cellular energy sources to bias the selectivity of the process. More generally, cells can control the relative availabilities of competing metal ions. For example, a cell can insert the weakly binding manganese ion (Mn2+) into a protein in the face of potential competition from strongly binding zinc (Zn2+) and copper ( Cu2+), because the cell keeps the cytoplasmic concentrations of zinc and copper thousands of times lower than that of manganese.
Berks 2008 Cells enforce an ion curtain Nature vol 455 pp 1043-4

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olive oil

In the FT weekend magazine March 7/8 2009 Joe Moran writes of Elizabeth David. In the drab period after the war in the late 1940s early 1950 Elizabeth Davis wrote A Book of Mediterranean Food. The beginning of a revolution in British cooking. Olive oil was only available in Chemists for removing wax from ears.

Serum vitamins and fruit and vegetable intake

Daucher et al , 20008, Relationships between different types of fruit and vegetable consumption and serum concentrations of antioxidant vitamins Brit Journal of Nutrition vol 100, 633-641
There is evidence of an inverse relationship between fruit and vegetable consumption and health . Many countries now recommend the consumption of at least five portion of fruits and vegetables (400 g) per day. Several mechanisms have been proposed to explain this positive association, including the increased intake of antioxidant compounds that are widely found in fruits and vegetables. Yet trials in which antioxidant micronutrients were taken at high doses over long periods have not confirmed a potential beneficial effect and even suggested harmful effects.
This study looks at the effect of different types of fruits and vegetables on serum vitamin antioxidant levels would be useful. Blood samples from 3521 subject (1487 men and 2034 women), aged 35-60 years participants were analysed for l3-carotene, vitamin C and a-tocopherol and completed at least six dietary records during the first 2 years of the study. Women had higher mean l3-carotene and vitamin C serum concentrations than men, but lower a-tocopherol serum concentration. Serum l3-carotene and vitamin C concentrations were positively correlated with consumption of both fruit and vegetable, as well as with most of the fruit and vegetable groups tested. These relationship persisted after adjustment for confounding factors. Regression analysis showed a linear dose-response relation hip. Root vegetables and citrus fruits were particularly associated with l3-carotene serum status as were citrus fruits for vitamin C. Fruit and vegetable consumption was either not or weakly associated with a-tocopherol serum concentrations.
The authors conclude that the association between fruit and vegetable intake were too weak to allow serum concentrations to be used as a measure of fruit and vegetable intake.

non protein coding RNAs

The control of enzymes and other proteins is of central metabolic import to nutrition.
The relationship between DNA, RNA and protein is no longer as simple as once thought - that specific genomic sequences are transcribed into messenger RNAs, which are then translated into proteins. It is now apparent that there is large and growing family of non-proteincoding RNAs (ncRNAs), with different mechanisms of their transcription and their role in regulating gene expression.
These single-stranded molecules are unstable. RNA I liable to chemical degradation and enzymatic cleavage, as well as to incomplete conversion back to DNA. The identification of ncRNAs in the past has often been dismissed as an artefacts. High-throughput genomics approaches, however, have begun to chart consistent patterns that are unlikely to be artefacts, and show several specific mechanisms for ncRNA biogenesis and processing.
The mechanisms by which ncRNAs are generated seem to be similar to those that operate during mRNA transcription and processing. Normally, the enzyme RNA polymerase II (Pol II) binds to the promoter sequence of a given gene to generate mRNA from the downstream genomic region. In a few cases, the 5' ends of genes on opposite DNA strands are located close together and so share the same promoter, which - when bound to Pol II bidirectionally triggers their transcription. These mRNAs, which are generally long, are also often translated into proteins. The latest studies report the widespread existence of ncRNAs in yeast, and mammalian cells, and show that these sequences originate from known promoters and can be transcribed in the opposite orientation to known genes.

Carninci P 2009 The long and short of RNAs Nature vol 457 , 974-5