Glukoneogeneseit is a pathway leading to the synthesis of glucose from pyruvate and other non-carbohydrate precursors, even in non-photosynthetic organisms.
It is found in all microorganisms, fungi, plants and animals and the reactions are essentially the same, leading to the synthesis of one molecule of glucose from two molecules of pyruvate. That's essentially how it isGlycolysisvice versa, which instead goes from glucose to pyruvate and shares seven enzymes with it.
Glukogenolysediffers greatly from gluconeogenesis: it does not lead toonce againProduction of glucose from non-carbohydrate precursors as shown by their general response:
Glycogen or (glucose)Norte→ n Glucose molecules
The following discussion focuses on the gluconeogenesis that occurs in higher animals and particularly in the mammalian liver.
- Why is gluconeogenesis important?
- Where does gluconeogenesis take place?
- Irreversible stages of gluconeogenesis
- From pyruvate to phosphoenolpyruvate
- Phosphoenolpyruvate precursors: pyruvate or alanine
- Phosphoenolpyruvate precursor: lactate
- From fructose-1,6-bisphosphate to fructose-6-phosphate
- From glucose-6-phosphate to glucose
- Gluconeogenesis: energetically expensive
- From pyruvate to phosphoenolpyruvate
- Coordinated regulation of gluconeogenesis and glycolysis.
- Regulation der Gluconeogenese
- PFK-1, FBPase-1 and fructose-2,6-bisphosphate
- PEP carboxiquinasa
- Regulation der Gluconeogenese
- Precursors of gluconeogenesis
- glucogenic amino acids
- Ketogenic Amino Acids
Why is gluconeogenesis important?
Gluconeogenesis is an essential metabolic pathway for at least two reasons.
- Ensures the maintenance of a reasonableblood sugar levelsif the liverGlycogenis almost sold out and nocarbohydratesYou will be taken.
- It is important to keep blood glucose within the normal range of 3.3 to 5.5 mmol/L (60 and 99 mg/dL) because many cells and tissues are highly or completely dependent on glucose for their ATP -to meet needs; Examples are red blood cells, neurons, skeletal muscles working in oxygen-poor conditions, renal medulla, testes, eye lens and cornea, and embryonic tissues. For example, the brain's glucose requirement is about 120 g/day, which corresponds to:
more than 50% of the whole body stores the monosaccharide, about 210 g, of which 190 g is stored in the liver andMuscle glycogen, and 20 g are found freely in body fluids;
about 75% of the daily requirement for glucose, about 160 g.
During fasting, between meals, or overnight, blood glucose levels remain in the normal range due to hepatic glycogenolysis and the release offatty acidsof adipose tissue and ketone bodies by the liver.fatty acidsand ketone bodies are preferentially utilized by skeletal muscle, thereby sparing glucose for glucose-dependent cells and tissues, primarily red blood cells and neurons. After about 18 hours of fasting or during intense and prolonged physical activityGlycogenReserves are exhausted and may no longer be sufficient. At this point, gluconeogenesis becomes important when carbohydrates are not ingested.
And the importance of gluconeogenesis is underscored by the fact that unconsciousness occurs at blood glucose levels below 2 mmol/L.
- Excretion of pyruvate would result in loss of ability to produce ATP through aerobic respiration, i.e. more than 10 molecules of ATP for every molecule of oxidized pyruvate.
Where does gluconeogenesis take place?
In higher animals, gluconeogenesis occurs in the liver, renal cortex, and epithelial cells of the small intestine, i. H. the enterocytes.
Quantitatively, the liver is the main site of gluconeogenesis, accounting for about 90% of synthesized glucose, followed by the renal cortex with about 10%. The liver's fundamental role is based on its size; In fact, based on wet weight, the renal cortex produces more glucose than the liver.
In the renal cortex, gluconeogenesis occurs in the cells of the proximal tubule, the part of the nephron that immediately follows the glomerulus. Much of the glucose produced in the kidney is utilized by the renal medulla, while the kidney's role in maintaining blood sugar levels becomes more important during prolonged fasting and liver failure. However, it must be emphasized that the kidneys, unlike the liver, do not have any significant glycogen stores and only contribute to maintaining blood sugar homeostasis through gluconeogenesis and not through glycogenolysis.
Part of the gluconeogenetic pathway also occurs in skeletal muscle, cardiac muscle and the brain, albeit to a very small extent. In adults, the muscle weighs about 18 times that of the liver; so yoursonce againGlucose synthesis can be of quantitative importance. However, the release of glucose into the circulation does not occur because, unlike the liver, renal cortex, and enterocytes, these tissues lack glucose-6-phosphatase (EC 188.8.131.52), an enzyme that catalyzes the final step in glucose circulation. (See below). .
Therefore, the production of glucose-6-phosphate, including glycogenolysis, does not contribute to the maintenance of blood sugar levels and only helps to replenish glycogen stores, which are small in the brain and mainly limited to astrocytes. For these tissues, particularly skeletal muscle due to its large mass, the contribution to blood glucose homeostasis arises only from the small amount of glucose released in the reaction catalyzed by enzymatic debranching (EC 184.108.40.206) of glycogenolysis .
In terms of cellular localization, most of the reactions take place in the cytosol, some in the mitochondria, and the final step) within the endoplasmic reticulum cisternae.
Irreversible stages of gluconeogenesis
As stated above, gluconeogenesis is essentially reverse glycolysis. And of the ten reactions that make up gluconeogenesis, seven are shared with glycolysis; These reactions have a ΔG close to zero and are therefore easily reversible. However, under intracellular conditions, the total ΔG for glycolysis is about -63 kJ/mol (-15 kcal/mol) and for gluconeogenesis about -16 kJ/mol (-3.83 kcal/mol). are irreversible.
The irreversibility of the glycolysis pathway is due to three highly exergonic reactions that cannot be used in gluconeogenesis, listed below.
- The phosphorylation of glucose to glucose-6-phosphate catalyzed by hexokinase (EC 220.127.116.11) or glucokinase (EC 18.104.22.168).
ΔG = -33,4 kJ/mol (-8 kcal/mol)
ΔG°' = -16,7 kJ/mol (-4 kcal/mol)
- Phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate catalyzed by phosphofructokinase-1 or PFK-1 (EC 22.214.171.124)
ΔG = -22,2 kJ/mol (-5,3 kcal/mol)
ΔG°' = -14,2 kJ/mol (-3,4 kcal/mol)
- The conversion of phosphoenolpyruvate or PEP to pyruvate catalyzed by pyruvate kinase (EC 126.96.36.199)
ΔG = -16,7 kJ/mol (-4,0 kcal/mol)
ΔG°' = -31,4 kJ/mol (-7,5 kcal/mol)
In gluconeogenesis, these three steps are bypassed by enzymes that catalyze irreversible steps towards glucose synthesis: this ensures the irreversibility of the metabolic pathway.
These reactions are discussed below.
From pyruvate to phosphoenolpyruvate
The first step in gluconeogenesis that bypasses an irreversible step in glycolysis, i. H. the reaction catalyzed by pyruvate kinase is the conversion of pyruvate to phosphoenolpyruvate.
Phosphoenolpyruvate is synthesized by two reactions catalyzed by enzymes in this order:
- Pyruvatcarboxylase (EC 188.8.131.52);
- Phosphoenolpyruvat-Carboxykinase oder PEP-Carboxykinase (EC 184.108.40.206).
Pyruvat → Oxalacetat → Phosphoenolpyruvat
Pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate using ATP. The enzyme requires the presence of magnesium or manganese ions.
Pyruvate + HCO3–+ ATP → Oxalacetat + ADP + PEU
Discovered by Merton Utter in 1960, the enzyme is a mitochondrial protein composed of four identical subunits, each with catalytic activity. The subunits contain a biotin prosthetic group covalently attached through an amide bond to the ε-amino group of a lysine residue, which acts as a carrier for activated CO.2during the reaction. An allosteric binding site for acetyl-CoA is also present on each subunit.
It should be noted that the pyruvate carboxylase catalyzed reaction leading to the production of oxaloacetate also provides intermediates for the citric acid cycle or Krebs cycle.
Phosphoenolpyruvate carboxykinase is present in approximately equal amounts in the mitochondria and cytosol of hepatocytes. Isoenzymes are encoded by separate nuclear genes.
The enzyme catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate in a reaction in which GTP acts as a high-energy phosphate donor. PEP carboxykinase requires the presence of magnesium and manganese ions. The reaction is reversible under normal cell conditions.
Oxalacetat + GTP ⇄ PEP + CO2+ BIP
This reaction produces CO2the same molecule that is added to pyruvate in the pyruvate carboxylase catalyzed reaction is removed. The carboxylation-decarboxylation sequence is used to activate pyruvate since decarboxylation of oxaloacetate facilitates the formation of phosphoenolpyruvate, making it thermodynamically viable.
More generally, the carboxylation-decarboxylation sequence strongly promotes endergonic reactions and also occurs in the citric acid cycle wherevia pentose phosphate, also called the hexose monophosphate pathway, and in the synthesis of fatty acids.
PEP carboxykinase levels are very low before birth, while their activity increases many-fold a few hours after birth. Because of this, gluconeogenesis is activated after birth.
The sum of the reactions catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase is:
Pyruvat + ATP + GTP + HCO3–→ PEP + ADP + PIB + PEU+CO2
ΔG°' of the reaction is equal to 0.9 kJ/mol (0.2 kcal/mol), while the standard free energy change associated with the formation of pyruvate from phosphoenolpyruvate by the kinase inversion of the pyruvate reaction is +31.4 kJ /mol (7.5 kcal/mol). Wart).
Although ΔG°' of the two steps leading to the formation of PEP from pyruvate is slightly positive, the actual free energy change (ΔG) calculated from the intracellular concentrations of the intermediates is strongly negative, -25 kJ/mol ( - 6 kcal/mol). This is due to the rapid consumption of phosphoenolpyruvate in other reactions, keeping its concentration at very low levels. Therefore, the synthesis of PEP from pyruvate is irreversible under cellular conditions.
It is important to note that the metabolic pathway for the formation of phosphoenolpyruvate from pyruvate depends on the precursor: pyruvate or alanine or lactate.
Phosphoenolpyruvate precursors: pyruvate or alanine
The shunt responses described below are predominant when the glucogenic precursor is alanine or pyruvate.
Pyruvate carboxylase is a mitochondrial enzyme, therefore pyruvate must be transported from the cytosol into the mitochondrial matrix. This is mediated by transporters located in the inner mitochondrial membrane called MPC1 and MPC2. ThisProteinWhen associated, they form a hetero-oligomer that facilitates the transport of pyruvate.
Pyruvate can also be produced from alanine in the mitochondrial matrix by transamination in the reaction catalyzed by alanine aminotransferase (EC 220.127.116.11), while the amino group is then converted to urea via the urea cycle.
Since the enzymes involved in the final stages of gluconeogenesis, with the exception of glucose-6-phosphatase, are cytosolic, oxaloacetate produced in the mitochondrial matrix is transported to the cytosol. However, there are no oxaloacetate transporters in the inner mitochondrial membrane. The passage to the cytosol occurs as a result of its reduction to malate, which, on the contrary, can pass through the inner mitochondrial membrane. The reaction is catalyzed by mitochondrial malate dehydrogenase (EC 18.104.22.168), an enzyme also involved in the citric acid cycle where the reaction occurs in reverse. In the reaction, NADH is oxidized to NAD.+.
Oxalacetat + NADH + H+⇄ Malate + NAD+
Although the ΔG°' of the reaction is highly positive, under physiological conditions the ΔG is close to zero and the reaction is easily reversible.
Malate crosses the inner mitochondrial membrane via a component of the malate-aspartate shuttle, the malate-α-ketoglutamate transporter. Once in the cytosol, malate is reoxidized to oxaloacetate in the reaction catalyzed by cytosolic malate dehydrogenase. In this NAD reaction+reduces NADH.
Malate + NAD+→ Oxalacetat + NADH + H+
Note: The malate-aspartate shuttle is the most active shuttle for transporting reducing NADH equivalents from the cytosol to the mitochondria. It is found in the mitochondria of the liver, kidneys and heart.
The reaction allows for the transport of mitochondrial reducing equivalents in the form of NADH into the cytosol. This transfer is necessary for gluconeogenesis because in the cytosol NADH, oxidized in the reaction catalyzed by glyceraldehyde-3-phosphate dehydrogenase (EC 22.214.171.124), occurs in very low concentrations with a [NADH]/[NAD+] ratio equals 8×10-4, about 100,000 times smaller than that observed in mitochondria.
Finally, oxaloacetate is converted to phosphoenolpyruvate in the reaction catalyzed by PEP carboxykinase.
Phosphoenolpyruvate precursor: lactate
Lactate is one of the most important gluconeogenic precursors. It is made for example by:
- red blood cells, which depend entirely on anaerobic glycolysis for ATP production;
- Skeletal muscle during intense physical activity, d. H. under oxygen starved conditions when the rate of glycolysis exceeds the rate of the citric acid cycle and oxidative phosphorylation.
If lactate is the gluconeogenic precursor, PEP synthesis occurs via a different pathway than previously seen. In the cytosol of NAD hepatocytes+the concentration is high and lactate is oxidized to pyruvate in the reaction catalyzed by the hepatic isoenzyme lactate dehydrogenase (EC 126.96.36.199). In the NAD reaction+reduces NADH.
Lactate + NAD+→ Pyruvate + NADH + H+
Production of cytosolic NADH obviates the need for export of reducing equivalents from mitochondria.
Pyruvate enters the mitochondrial matrix to be converted to oxaloacetate in the reaction catalyzed by pyruvate carboxylase. In mitochondria, oxaloacetate is converted to phosphoenolpyruvate in the reaction catalyzed by mitochondrial pyruvate carboxylase. Phosphoenolpyruvate leaves the mitochondria via an anion transporter located in the inner mitochondrial membrane and, once in the cytosol, continues on the pathway of gluconeogenesis.
Note: The synthesis of glucose from lactate can be considered part of theChoriclusthat occurs in the liver.
From fructose-1,6-bisphosphate to fructose-6-phosphate
The second step in gluconeogenesis, bypassing an irreversible step in the glycolysis pathway, ie the reaction catalyzed by PFK-1, is the dephosphorylation of fructose-1,6-bisphosphate to fructose-6-phosphate.
This reaction, catalyzed by fructose-1,6-bisphosphatase or FBPasi-1 (EC 188.8.131.52), a Mg2+Dependent enzyme located in cytosol leads to hydrolysis of C-1-phosphate from fructose-1,6-bisphosphate, without ATP production.
Fructose-1,6-bisphosphat + H2O → Fructose-6-Phosphate + PEU
The ΔG°' of the reaction is -16.3 kJ/mol (-3.9 kcal/mol), so it is an irreversible reaction.
From glucose-6-phosphate to glucose
The third step in gluconeogenesis, which bypasses an irreversible step in the glycolysis pathway, ie the reaction catalyzed by hexokinase or glucokinase, is the dephosphorylation of glucose-6-phosphate to glucose.
This reaction is catalyzed by the catalytic subunit of glucose-6-phosphatase, a protein complex found in the endoplasmic reticulum membrane of hepatocytes, enterocytes and renal proximal tubular cells. The glucose-6-phosphatase complex consists of a glucose-6-phosphate catalytic subunit and a glucose-6-phosphate transporter called glucose-6-phosphate translocase or T1.
The catalytic subunit of glucose-6-phosphatase has its active site on the luminal side of the organelle. That is, the enzyme catalyzes the release of glucose not into the cytosol but into the lumen of the endoplasmic reticulum.
Glucose-6-phosphate is localized both from gluconeogenesis arising in the reaction catalyzed by glucose-6-phosphate isomerase or phosphoglucose isomerase (EC 184.108.40.206) and from glycogenolysis arising in that catalyzed by phosphoglucomutase Reaction (EC 220.127.116.11) arises. . . . in the cytosol and must enter the lumen of the endoplasmic reticulum to be dephosphorylated. Its transport is mediated by glucose-6-phosphate translocase.
The catalytic subunit of glucose-6-phosphatase, a Mg2+As an enzyme-dependent enzyme, it catalyzes the final step in both gluconeogenesis and glycogenolysis. And like the reaction catalyzed by fructose-1,6-bisphosphatase, this reaction results in the hydrolysis of a phosphate ester.
Glucose-6-Phosphat + H2O → Glucose + PEU
It should also be noted that due to the orientation of the active site, the cell separates this enzymatic activity from the cytosol, preventing the glycolysis taking place in the cytosol from being terminated by the enzymatic action on glucose-6-phosphate.
The ΔG°' of the reaction is -13.8 kJ/mol (-3.3 kcal/mol), so it is an irreversible reaction. Conversely, if the reaction were instead catalyzed by hexokinase/glucokinase, transfer of a phosphate group from glucose-6-phosphate to ADP would be required. Such a reaction would have a ΔG of +33.4 kJ/mol (+8 kcal/mol) and would therefore be strongly endergonic. Similar considerations can be made for the FBPase-1 catalyzed reaction.
glucose and PEUThe group appears to be transported to the cytosol by different transporters termed T2 and T3, the latter being an anion transporter.
Finally, glucose leaves the hepatocytes via the GLUT2 membrane transporter, enters the bloodstream, and is transported to the tissues that need it. In contrast, under physiological conditions, as mentioned above, the glucose produced by the kidney is mainly used by the renal medulla.
Gluconeogenesis: energetically expensive
As with glycolysis, much of the energy consumed is consumed in the irreversible phases of the process.
Six high-energy phosphate bonds are consumed: two by GTP and four by ATP. In addition, two molecules of NADH are required for the reduction of two molecules of 1,3-bisphosphoglycerate in the reaction catalyzed by glyceraldehyde-3-phosphate dehydrogenase. The oxidation of NADH causes the lack of production of 5 ATP molecules, which are synthesized when the electrons of the reduced coenzyme are used in oxidative phosphorylation.
Furthermore, these energetic considerations show that gluconeogenesis is not simply reverse glycolysis, in which case it would require the consumption of two molecules of ATP, as shown by the general glycolysis equation.
Glukose + 2 ADP + 2 PEU+ 2 NAD+→ 2 Pyruvato + 2 ATP + 2 NADH + 2 H++ 2 hours2Ö
Here is the general equation for gluconeogenesis:
2 Pyruvate + 4 ATP + 2 GTP + 2 NADH++ 2 hours++ 4 hours2O → Glukose + 4 ADP + 2 BIP + 6 PEU+ 2 NAD+
At least in the liver, the ATP needed for gluconeogenesis comes primarily from the oxidation of fatty acids or the carbon skeletons of amino acids, depending on the "fuel" available.
Coordinated regulation of gluconeogenesis and glycolysis.
If glycolysis and gluconeogenesis were active simultaneously at high rates in the same cell, the only products would be ATP consumption and heat production, particularly in the irreversible steps of both pathways, and nothing else.
For example, considering PFK-1 and FBPasi-1:
ATP + Fructose-6-phosphate → ADP + Fructose-1,6-bisphosphate
Fructose-1,6-bisphosphat + H2O → Fructose-6-Phosphate + PEU
The sum of the two reactions is:
ATP + H2O → ADP + PEU+ heat
Two reactions occurring simultaneously in opposite directions result in a waste cycle or substrate cycle. These seemingly pointless cycles allow for the regulation of opposing metabolic pathways. In fact, different enzymes are involved in a substrate cycle, at least two whose activity can be regulated separately. Such regulation would not be possible if a single enzyme acts in both directions. The activity of the enzymes involved is modulated by:
- allosteric mechanisms;
- covalent modifications such as phosphorylation and dephosphorylation;
- Changes in the concentration of the enzymes involved due to changes in their synthesis/degradation ratio.
Allosteric mechanisms are very fast and immediately reversible, occurring within milliseconds. The others, triggered by signals from outside the cell, such as hormones such as insulin, glucagon, or epinephrine, occur on a time scale of seconds or minutes, and hours with changes in enzyme concentration.
This allows coordinated regulation of the two pathways and ensures that when pyruvate enters gluconeogenesis, the flow of glucose through the glycolytic pathway is slowed and vice versa.
Regulation der Gluconeogenese
The regulation of gluconeogenesis and glycolysis involves the unique enzymes of each pathway, not the common ones.
While the main checkpoints of glycolysis are the reactions catalyzed by PFK-1 and pyruvate kinase, the main checkpoints of gluconeogenesis are the reactions catalyzed by fructose-1,6-bisphosphatase and pyruvate carboxylase.
The other two enzymes unique to gluconeogenesis, glucose-6-phosphatase and PEP-carboxykinase, are regulated at the transcriptional level.
In mitochondria, pyruvate can be converted into:
- Acetyl-CoA, in reactions catalyzed byPyruvate Dehydrogenase Complex, reaction linking glycolysis to the Krebs cycle;
- Oxaloacetate, in the reaction catalyzed by pyruvate carboxylase to continue the gluconeogenesis pathway.
The metabolic fate of pyruvate depends on the availability of acetyl-CoA, ie the availability of fatty acids in the mitochondria.
When fatty acids are available, their β-oxidation leads to the production of acetyl-CoA, which enters the Krebs cycle and leads to the production of GTP and NADH. When the cell's energy needs are met, oxidative phosphorylation decreases, [NADH]/[NAD+] increases, NADH inhibits the citric acid cycle, and acetyl-CoA accumulates in the mitochondrial matrix. Acetyl-CoA is a positive allosteric effector of pyruvate carboxylase and a negative allosteric effector of pyruvate kinase. In addition, it inhibits the pyruvate dehydrogenase complex both through feedback inhibition and through phosphorylation through activation of a specific kinase.
This means that when the cell is subjected to a high energy load, the formation of acetyl-CoA from pyruvate decreases, while the conversion of pyruvate to glucose is stimulated. Therefore, acetyl-CoA is a molecule that indicates that no further oxidation of glucose is required for energy production and that glucogenic precursors can be used for glucose synthesis and storage.
On the other hand, when acetyl-CoA levels fall, the activity of pyruvate kinase and the pyruvate dehydrogenase complex increases, and with it the flux of metabolites through the citric acid cycle. This supplies energy to the cell.
In summary, when the cell is under high energy load, pyruvate carboxylase is active since the first checkpoint of gluconeogenesis determines the fate of pyruvate in the mitochondria.
The second important control point in gluconeogenesis is the reaction catalyzed by fructose-1,6-bisphosphatase. The enzyme is allosterically inhibited by AMP. When AMP levels are high and consequently ATP levels are low, gluconeogenesis decreases. This means that, as seen above, FBPase-1 is active when the cell's energy load is high enough to support itonce againGlukosesynthese.
In contrast, PFK-1, the corresponding glycolytic enzyme, is allosterically activated by AMP and ADP and allosterically inhibited by ATP and citrate, the latter as a result of the condensation of acetyl-CoA and oxaloacetate. For this reason:
- when AMP levels are high, gluconeogenesis decreases and glycolysis accelerates;
- When ATP levels are high, or when acetyl-CoA or citrate are present in sufficient concentrations, gluconeogenesis is promoted while glycolysis is slowed.
Elevated levels of citrate indicate that citric acid cycle activity may be decreasing; In this way, pyruvate can be used in the synthesis of glucose.
PFK-1, FBPase-1 and fructose-2,6-bisphosphate
The liver plays a key role in maintaining blood sugar homeostasis: this requires regulatory mechanisms that coordinate the consumption and production of glucose. Two hormones are mainly involved: glucagon and insulin. They act intracellularly through fructose-2,6-bisphosphate or F2,6BP, an allosteric effector of PFK-1 and FBPase-1. This molecule is structurally related to fructose-1,6-bisphosphate but is not an intermediate in glycolysis or gluconeogenesis.
It was discovered in 1980 by Emile Van Schaftingen and Henri-Gery Hers as a potent activator of PFK-1. The following year, the same researchers showed that it is also a potent FBPase-1 inhibitor.
When fructose-2,6-bisphosphate binds to the allosteric site of PFK-1, it decreases the enzyme's affinity for ATP and citrate, allosteric inhibitors, while increasing the enzyme's affinity for fructose-6-phosphate, its substrate PFK- 1 is practically inactive in the absence of fructose-2,6-bisphosphate and in the presence of physiological concentrations of ATP, fructose-6-phosphate, and the allosteric effectors AMP, ATP, and citrate. On the other hand, the presence of fructose-2,6-bisphosphate activates PFK-1 and thus stimulates glycolysis in hepatocytes. At the same time, fructose-2,6-bisphosphate delays gluconeogenesis by inhibiting fructose-1,6-bisphosphate even in the absence of AMP. However, the effects of fructose-2,6-bisphosphate and AMP on FBPase-1 activity are synergistic.
The concentration of fructose-2,6-bisphosphate is regulated by the relative rates of synthesis and breakdown. It is synthesized from fructose-6-phosphate in the reaction catalyzed by phosphofructokinase-2 or PFK-2 (EC 18.104.22.168) and to fructose-6-phosphate in the reaction catalyzed by fructose-2,6-bisphosphatase or FBPasi-2 hydrolyzed (EC 22.214.171.124). These two enzyme activities reside in a single bifunctional enzyme or tandem enzyme. In the liver, the balance of these two enzyme activities is regulated by insulin and glucagon, as described below.
It's released into the system when blood sugar levels drop, signaling the liver to increase and decrease the use of glucose for its own needsonce againSynthesis of glucose and its release from glycogen stores.
After binding to specific membrane receptors, glucagon stimulates hepatic adenylate cyclase (EC 126.96.36.199) to synthesize 3',5'-cyclic AMP or cAMP, which activates cAMP-dependent protein kinase or protein kinase A or PKA (EC188.8.131.52). ). The kinase catalyzes the phosphorylation of a specific serine residue (Ser32) of PFK-2/FBPase-2. As a result of phosphorylation, phosphatase activity increases while kinase activity decreases. This reduction due to the increase in KMetrofructose-6-phosphate causes a decrease in fructose-2,6-bisphosphate levels, which in turn inhibits glycolysis and stimulates gluconeogenesis. Therefore, in response to glucagon, the liver produces more glucose, allowing the organ to counteract the drop in blood sugar levels.
Note: Like adrenaline, glucagon stimulates gluconeogenesis by also increasing the availability of substrates such as glycerol and amino acids.
After binding to specific membrane receptors, insulin activates a protein phosphatase, phosphoprotein phosphatase 2A or PP2A, which catalyzes the removal of the phosphate group from PFK-2/FBPase-2, thereby increasing PFK-2 activity and decreasing PFK-2 activity. 2nd -2 activity. (At the same time, insulin also stimulates a cAMP phosphodiesterase, which hydrolyzes cAMP to AMP.) This increases the level of fructose-2,6-bisphosphate, which in turn inhibits gluconeogenesis and stimulates glycolysis.
In addition, fructose-6-phosphate allosterically inhibits FBPase-2 and activates PFK-2. It should be noted that the activities of PFK-2 and FBPase-2 are inhibited by their reaction products. However, the main effectors are the level of fructose-6-phosphate and the phosphorylation state of the enzyme.
In contrast to pyruvate carboxylase and fructose-1,6-bisphosphatase, the catalytic subunit of glucose-6-phosphatase is not subject to allosteric or covalent regulation. Its activity is modulated at the transcriptional level. Low blood sugar and glucagon, that is, factors that lead to increased glucose production, and glucocorticoids stimulate their synthesis, which, on the contrary, is inhibited by insulin.
Also the k.Metrofor glucose-6-phosphate is significantly larger than the range of physiological concentrations for glucose-6-phosphate itself. Therefore, it is said that the activity of the enzyme depends almost linearly on the concentration of the substrate, ie the enzyme is controlled by the substrate level.
The enzyme is mainly regulated at the level of synthesis and degradation. For example, high levels of glucagon or fasting increase protein production, stabilize your mRNA, and increase your transcription rate. Elevated levels of glucose or insulin in the blood have adverse effects.
Xylulose-5-phosphate, a product of the pentose phosphate pathway, is a recently discovered regulatory molecule. Stimulates glycolysis and inhibits gluconeogenesis by controlling fructose-2,6-bisphosphate levels in the liver.
If the blood sugar level rises, e.g. After a carbohydrate-rich meal, activation of the glycolysis and hexose monophosphate pathways in the liver occurs. The xylulose-5-phosphate produced activates protein phosphatase 2A which, as indicated above, dephosphorylates PFK-2/FBPase-2, inhibits FBPase-2 and stimulates PFK-2. This leads to an increase in the concentration of fructose-2,6-bisphosphate and then to the inhibition of gluconeogenesis and stimulation of glycolysis, resulting in increased production of acetyl-CoA, the main substrate forLipidSynthesis. At the same time, there is increased flux through the hexose monophosphate shunt, resulting in the production of NADPH, a source of electrons forLipidSynthesis. Finally, PP2A also dephosphorylates carbohydrate-sensitive element-binding protein, or ChREBP, a transcription factor that activates expression of liver genes for lipid synthesis. Therefore, in response to an increase in blood sugar levels, lipid synthesis is stimulated.
Therefore, it is clear that xylulose-5-phosphate is an important regulator of carbohydrate and fat metabolism.
Precursors of gluconeogenesis
Besides the already mentioned pyruvate, the main gluconeogenic precursors are lactate, glycerol, most amino acids and in general any compound that can be converted intoPyruvateo Oxalacetat.
Glycerin is released throughLipolysisin adipose tissue. With the exception of propionyl-CoA, it is the only usable part of the lipid moleculeonce againGlucose synthesis in animals.
Glycerol enters gluconeogenesis or glycolysis, depending on the cellular energy load, as dihydroxyacetone phosphate, or DHAP, which is synthesized in two steps.
In the first step, glycerol is phosphorylated to glycerol-3-phosphate in the reaction catalyzed by glycerol kinase (EC 184.108.40.206) using an ATP.
Glycerin + ATP → Glycerin-3-phosphat + ADP + PEU
The enzyme is absent from adipocytes but is present in the liver; This means that glycerol must reach the liver to be further metabolized.
Glycerol-3-phosphate is then oxidized to dihydroxyacetone phosphate in a reaction catalyzed by glycerol-3-phosphate dehydrogenase (EC 220.127.116.11). In this NAD reaction+reduces NADH.
Glycerin-3-phosphat + NAD+⇄ Diidroxiacetona fosfato + NADH + H+
During prolonged fasting, glycerol is the main gluconeogenic precursor, accounting for about 20% of glucose production.
glucogenic amino acids
Pyruvate and oxaloacetate are the gateways for glucogenic amino acids, i.e. those whose carbon skeleton or parts of it can be usedonce againGlukosesynthese.
Amino acids result from the catabolism ofProtein, both from food and from endogenous proteins such as those from skeletal muscle in the fasted state or during intense and prolonged exercise.
The catabolic processes of each of the twenty amino acids that make up proteins converge to form seven major products: acetyl-CoA, acetoacetyl-CoA, α-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate, and pyruvate.
Except acetyl-CoA, acetoacetyl-CoA, the other five molecules can be used for gluconeogenesis. This means that gluconeogenic amino acids can also be defined as those whose carbon skeleton or parts thereof can be converted into one or more of the above-mentioned molecules.
Entry points for gluconeogenic amino acids are shown below.
- Pyruvate: Alanine, Cysteine, Glycine, Serine, Threonine and Tryptophan.
- Oxaloacetate: aspartate and asparagine.
- α-Ketoglutarate: Glutamate, Arginine, Glutamine, Histidine und Proline.
- Succinyl-CoA: Isoleucin, Methionin, Threonin und Valin.
- Fumarate: phenylalanine and tyrosine.
Citric acid cycle intermediates, α-ketoglutarate, succinyl-CoA and fumarate enter the gluconeogenic pathway after conversion to oxaloacetate.
The use of the carbon skeletons of amino acids requires the removal of the amino group. Alanine and glutamate, key molecules in the transport of amino groups from extrahepatic tissues to the liver, are the major glucogenic amino acids in mammals. Alanine is the main gluconeogenic substrate in the liver; This amino acid is transported through the muscle liver and other peripheral tissuesGlucose-Alanine Cycle.
Ketogenic Amino Acids
Acetyl-CoA and acetoacetyl-CoA cannot be used for gluconeogenesis and are precursors to fatty acids and ketone bodies. The stoichiometry of the citric acid cycle makes it clear why they can't get used to itonce againGlukosesynthese.
Acetyl-CoA condenses in the citrate synthase-catalyzed reaction with oxaloacetate to form citrate, a 6-carbon molecule instead of 4 like oxaloacetate. However, although the two carbon atoms of acetyl-CoA become part of the oxaloacetate molecule, two carbon atoms are oxidized and eliminated as CO.2, in reactions catalyzed by isocitrate dehydrogenase (EC 18.104.22.168) and the α-ketoglutarate dehydrogenase complex. Therefore, acetyl-CoA creates no net carbon gain for the citric acid cycle.
Furthermore, the reaction leading to the formation of acetyl-CoA from pyruvate and catalyzed by the pyruvate dehydrogenase complex, which is the bridge between glycolysis and the Krebs cycle, is irreversible and there is no other pathway, acetyl-CoA to convert in pyruvate.
Pyruvate + NAD++ CoASH → Acetyl-CoA + NADH + H++C02
For this reason, amino acids whose breakdown produces acetyl-CoA and/or acetoacetyl-CoA are called ketogenic.
Only leucine and lysine are uniquely ketogenic.
Note: Plants, yeast and many bacteria can use acetyl-CoAonce againGlucose synthesis as they possess the glyoxylate cycle. This cycle shares four reactions with the citric acid cycle, two unique enzymes, isocitrate lyase (EC22.214.171.124) and malate synthase (EC 126.96.36.199), but lacks the decarboxylation reactions. Therefore, organisms possessing this pathway can utilize fatty acids for gluconeogenesis.
Five amino acids, isoleucine, phenylalanine, tyrosine, threonine, and tryptophan, are glucogenic and ketogenic because part of their carbon structure can be used for gluconeogenesis while the other gives rise to ketone bodies.
Propionate, a three-carbon fatty acid, is a gluconeogenic precursor because, like propionyl-CoA, the active molecule, it can be converted to succinyl-CoA.
The various sources of propionate are discussed below.
- It can arise from the β-oxidation of odd-chain fatty acids such as margaric acid, asaturated fatty acidwith 17 carbon atoms. These fatty acids are rare compared to monochain fatty acids, but they are present in the fatty acid in significant amountsLipidossome marine organisms, ruminants and plants. In the final step of the β-oxidation sequence, the substrate is a five-carbon fatty acid. This means that once oxidized and split into two fragments, it produces acetyl-CoA and propionyl-CoA.
- Another source is the oxidation of branched chain fatty acids, where alkyl branches have an odd number of carbon atoms. An example is phytanic acid, which is produced in ruminants by the oxidation of phytol, a breakdown product of chlorophyll.
- In ruminants, propionate is also made from glucose. Glucose is released as cellulose is broken down by bacterial cellulase (EC 188.8.131.52) in the rumen, one of the four chambers that make up the stomach of these animals. These microorganisms then ferment to convert glucose into propionate, which after absorption can be used for gluconeogenesis, fatty acid synthesis, or for energy.
In ruminants, where gluconeogenesis tends to be a continuous process, propionate is the main gluconeogenic precursor.
- Propionate can also arise from the breakdown of valine, leucine, and isoleucine (see above).
The oxidation of propionyl-CoA to succinyl-CoA involves three reactions that occur in the liver and other tissues.
In the first reaction, propionyl-CoA is carboxylated to D-methylmalonyl-CoA in the reaction catalyzed by propionyl-CoA carboxylase (EC 184.108.40.206), an enzyme that requires biotin. This reaction consumes one ATP.
Propionyl-CoA + HCO3–+ ATP → D-Methylmalonyl-CoA+ ADP + PEU
In the subsequent reaction, catalyzed by methylmalonyl-CoA epimerase (EC 220.127.116.11), D-methylmalonyl-CoA epimerizes to its L-stereoisomer.
D-Methylmalonyl-CoA ⇄ L-Methylmalonyl-CoA
Finally, L-methylmalonyl-CoA undergoes intramolecular rearrangement to succinyl-CoA in the reaction catalyzed by methylmalonyl-CoA mutase (EC 18.104.22.168). This enzyme requires 5-deoxyadenosylcobalamin or coenzyme B12, a derivative of cobalamin or vitamin B12, as a coenzyme.
L-Methylmalonyl-CoA ⇄ Succinyl-CoA
- Bender DA Introduction to nutrition and metabolism. 3. Edition. Taylor and Francisco, 2004
- Garrett R. H., Grisham C. M. Biochemie. 4. Auflage. Brooks/Cole, Cengage Learning, 2010
- Kabashima T, Kawaguchi T, Wadzinski BE, Uyeda K. Xylulose-5-phosphate mediates glucose-induced lipogenesis by xylulose-5-phosphate-activated protein phosphatase in rat liver. Proc Natl Acad Sci USA 2003;100:5107-5112. make:10.1073/pnas.0730817100
- Kuriyama H. and all. Coordinated regulation of lipid-specific and liver-specific glycerol channels, lipid aquaporin and aquaporin 9. Diabetes 2002;51(10):2915-2921. make:10.2337/diabetes.51.10.2915
- McCommis KS and Finck B.N. Mitochondrial pyruvate transport: a historical perspective and future lines of research. Biochem J. 2015;466(3):443-454. dependency:10.1042/BJ20141171
- Nelson D.L., M.M. Cox M.M. Lehninger. principles of biochemistry. 6th edition. WH Freeman and Company, 2012
- Rosenthal M.D., Glew R.H. Medicinal Biochemistry: The Human Metabolism in Health and Disease. John Wiley J. & Sons, Inc., publication, 2009
- Soty M, Chilloux J, Delalande F, Zitoun C, Bertile F, Mithieux G, and Gautier-Stein A. Post-translational regulation of the glucose-6-phosphatase complex by cyclic adenosine monophosphate is a critical determinant of endogenous glucose production and is controlled by the glucose-6-phosphate transporter. J Proteome Res 2016;15(4):1342-1349. make:10.1021/acs.jproteoma.6b00110
- Stipanuk M.H., Caudill M.A. Biochemical, physiological and molecular aspects of human nutrition. 3. Edition. Elsevier Health Sciences, 2012
- Van Schaftingen E. and Hers H-G. Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate. Proc Natl Acad Sci USA 1981;78(5):2861-2863. make:10.1073/pnas.78.5.2861
- Van Schaftingen E, Jett MF, Hue L and Hers HG. Control of hepatic 6-phosphofructokinase by fructose-2,6-bisphosphate and other effectors. Proc Natl Acad Sci USA 1981;78(6):3483-3486. make:10.1073/pnas.78.6.3483


Neuro Marketing Part One
Have you ever wondered why you notice some adverts and not others?
The reptilian brain is thought to be the oldest evolutionary area and sits in the centre surrounded by the Limbic System and Neocortex. Our basic instinctive systems are stored in the reptilian brain. It passes messages to the limbic part of the brain, stating if it is hungry, cold, hot, thirsty, in pain, happy, sad, if it should be aggressive, submissive, or sexually aroused. The limbic brain controls messages in and out of the reptilian brain so that we are protected from the reptilian instincts. The limbic brain is responsible for pleasure, and pain.
Why might this information be useful to people working in the copywriting or marketing industries?
Knowing how people react to things and how to make a connection with them will give you a better chance of influencing their decisions, or thoughts. Connecting with a person’s reptilian brain can be done through making them angry, aggressive, or sexually aroused. If you think about the advertisements that are promoted by large marketing companies, they often use images that connect with the reptilian brain. Sexually alluring female and male models, promises of improving your ability to attract a sexual mate, pictures of food designed to trigger your need for tasty food.
The reptilian brain is responsive to images, one reason for this is that the optic nerve connects right into this area of the brain. This does not mean that the reptilian brain only responds to images, written words can create an image in the mind that is just as strong as visual stimulation.
Many marketers use target the reptilian brain as it is easy to fool and it connects with our primal desires. Look at the image below, do you see a spiral or circles?
Your reptilian brain is telling you that you’re seeing a spiral, but the reality is that you are looking at several circles.
So, as a content writer, or marketer, here are a few things you should know about the reptilian brain :
- Your reptilian brain is self-centred, it’s all about YOU!
- It’s always on, if you want to get something noticed then use images or words that connect with the reptilian brain. Sex, food, aggression, fear…
- It controls your routines and habits
- It connects with the emotional brain
- Instinct and arousal are linked to the reptilian brain
- Desire and need are often stronger motivating factors than logic
If you want to produce content that converts and influences your audience then try to connect with their reptilian brain. You might be pleasantly surprised how influential it can be.
Further information on neuromarketing will be added to the blog very soon, so keep checking back, or add your name to the subscription list.


We enable laboratory precision at high volume throughput
Making sure that drugs are released in the affected part of the body and at a specific rate is a huge challenge, because the size of the capsules that deliver these active ingredients is uncontrollable. At Microcaps we developed a patented technology that enables the size control of these microcapsules with Swiss precision, hence they all behave exactly the same. This means we can directly tailor and predict the release profile of a drug. Our solution is also highly relevant for fragrances, flavors and probiotics.


Not so long ago a friend of mine, Paul Bower came across a second hand copy of a book by Desmond Morris called the Human Zoo. Written in 1969 it is a book that reflect’s his generations misgivings about cities. The central premise of the book is that the human animal evolved to live in hunter-gatherer groups of around 60 people. This extended family group would need around 20 square miles to support its needs. Today the same area could accommodate a city of 6 million people crammed together in a way that human are unable to cope with. This, he argues, is not natural and it is hardly surprising that some people in cities act a little strangely. Indeed Morris equates this strange behaviour to the compulsive traits exhibited by many animals when they are confined in zoos; mental health disorders, sexual perversion, violence etc… Hence in Morris’s eyes the modern city is the human zoo.
However the books conclusion is not entirely negative. Morris suggests that the remarkable aspect of city living is that most of us don’t exhibit this compulsive behaviour. We have moved from living with 59 neighbours to 5,999,999 in the blick of an evolutionary eye and have coped extremely well. As he says; “The least experienced zoo director would never contemplate cramming and cramping a group of animals to the extent that man has crammed and cramped himself into his modern cities and towns. By all the rules the human zoo should be a screaming madhouse… cynics may argue that this is indeed the case, but plainly it is not. …aberrant behaviour is startling, not for its existence but for its rarity”.
Indeed Morris goes on to argue that the secret to human success as a species is that we actually thrive on these conditions: “Just as colonies of nesting seabirds are reproductively aroused by massing in dense breeding communities, so the human animal is intellectually aroused by massing in dense urban communities. They are breeding colonies of human ideas.”


The breast structure in men is slightly different from that of women.
While the breast tissue is larger in women, the situation is different in men. In some cases, there can be complaints in the breast area of men for various reasons. Gynecomastia is one of these complaints.
What is gynecomastia?
Gynecomastia is the name given to the enlargement and swelling of breast tissue compared to normal in men. Along with these symptoms, a lump under the nipple, nipple discharge, pain and sensitivity to pressure in the breasts can be seen.
The cause of gynecomastia is most likely hormonal. Both men and women have estrogen and testosterone hormones, but while the testosterone ratio in men is high, estrogen secretion in women is high. Gynecomastia occurs when the testosterone-estrogen balance in men is disturbed and estrogen is excreted above normal levels. Hormones are not the only cause of gynecomastia. Obesity, incorrect eating habits, kidney failure and liver disease, hyperthyroidism, tumors in the testicles or adrenal glands, drug and alcohol consumption can also cause gynecomastia. Gynecomastia can be observed in cases of extreme hunger, as testosterone decreases and estrogen remains constant. And some of the drugs used trigger this situation.
Gynecomastia is not a cancer. It is benign and is a breast enlargement. While it is not harmful to health, men with gynecomastia may feel embarrassed and uncomfortable. Gynecomastia that does not disappear on its own or with medication can be treated with gynecomastia surgery because of its psychological effects.
How is a gynecomastia operation performed?
If the person is diagnosed with gynecomastia or if the person suspects this situation, he or she contacts health care institutions and if the doctor considers it appropriate, surgery can be performed.
- The breast tissue of the anesthetized patient is first examined endoscopically.
- Gynecomastia can only occur in the form of swelling of the granular tissue, i.e. in the form of hard breast tissue, both granular and fatty, and only an increase in fatty tissue.
- In gynecomastia, excess tissue is removed with surgical procedures, which are caused by an increase in the amount of granular tissue. If it is accompanied by fatty tissue, the procedure is performed with liposuction. If only the fatty tissue has increased, liposuction is sufficient.
- If granular tissue is to be removed, the breast is opened in the middle, skin and tissue are removed, the nipple is reduced and closed.
- Excess tissue is removed according to the method considered appropriate by the surgeon, the incised areas are sutured and the surgery is finished.
Why gynecomastia surgery?
- It allows the removal of gynecomastia with the clearest and most accurate results.
- If the person suffers from gynecomastia for a long period of time, it does not regress by itself. Therefore, a surgical procedure is necessary to treat gynecomastia.
- A very thin and small surgical scar may remain on the chest, but it is not aesthetically disturbing. If the person later does bodybuilding, it is not even visible, as it is right at the border of their pectoral muscles.
- – The feelings of embarrassment that men feel due to the growth of their breasts and the person’s aesthetic concerns and feeling of discomfort are eliminated.
- – No long healing period is necessary.
Who is a gynecomastia operation suitable for?
- For the treatment of gynecomastia that occurs in one or both breasts.
- Since it can occur in infancy and old age, adolescence is the most common period in gynecomastia. It is the case when the baby has gynecomastia in the womb due to the estrogens of the mother. In male babies with developed breasts, this situation goes away by itself within 3 weeks at the latest.
- Adolescence is a time when the hormones in the body are very different. It is observed because of the high hormone activity and it passes 6 to 24 months after entering puberty.
- Since gynecomastia in infancy and adolescence passes after a certain period of time, no immediate surgery is required. An operation can be performed in case of gynecomastia that occurs at an advanced age and has existed for a long time.
- Since a non-progressive gynecomastia can be controlled with medication or hormone therapy, no surgery is necessary.
- A gynecomastia operation can be performed after the age of 17. Nevertheless, it is advisable to wait until the age of 18.
After a gynecomastia operation
- Gynecomastia corsets are used for a while after the operation according to the doctor’s recommendations. This corset is always worn for at least 3 weeks. Until an average of the 6th week, the use of a corset is important for healing if you move during the day or if heavy exercises are to be performed.
- If a liposuction operation is performed, the person can return almost completely to their daily life after 3 weeks.
- If a surgical procedure is performed, the person can be discharged on the same day. Stays in hospital for 1 day if necessary.
- Lying on the stomach should be avoided for 1 week.
- Edema and swelling can be observed in the surrounding area. At the end of a week these symptoms disappear. Some creams can be applied to the area on the doctor’s recommendation. Medications prescribed by the doctor are used for pain and the pain is controlled.
- During the first 3 days, the person should rest, not move shoulders and arms as much as possible and not take a shower. After 3 days a warm and short shower can be taken. After this time, depending on the state of health, the person is able to do light exercises and return to their daily life.
- Activities like sauna, Turkish bath, solarium and steam bath must be avoided for up to 6 weeks.


Tree InjectionsBy Weldon Stanford | August 31, 2016 | services
Tree injection is exactly what it sounds like, a shot for your tree. Pesticides have received a lot of negative attention over the years but still remain a necessity for the health and sometimes life of your plants. Tree injections are the environmentally safe way to treat your trees while protecting your home, business and the planet.
Trunk injections are given using a special tool, often resembling a large syringe, which is inserted in the bottom 18 inches of the trunk at entry points around 6 inches apart. This is an extremely unobtrusive method as the injection only penetrates up to 1 5/8 inch. If your tree is approximately 20 inches in diameter, it will need around a 3-ounce injection that will sustain it for nearly two years! Not only can tree injections deliver pesticides for prevention, the injection can be given amid a full infestation and often save the tree. There are also fertilizer injections that can help trees which are struggling by putting the necessary nutrients directly into their vascular flow. Today’s soil, yards and properties are not as nutrient dense due to our constant maintenance and removal of twigs, leaves and decaying plants which feed the soil. Land with sod actually leeches most of the nutrients from the existing soil to feed the new grass. For this reason, fertilizer injections have become key in the survival of many older trees.
As for injections for prevention or elimination of harmful insects, the method is the least invasive available and uses the lowest amount of pesticides for treatment. When injected into the tree, the chemicals are sealed inside and do not risk exposure to other plants or animals. There have also been numerous studies showing that pesticide injections are safe for food bearing trees as most of the chemicals divert to the foliage. This will become the more environmentally approved method of guarding mass food crops from pesticides in the near future.


A New Therapeutic Approach
How It Works
The components of AXS-05, DM and bupropion, each target different CNS receptor systems. Combining the distinct and independent mechanisms of action of these two compounds may be useful in the treatment of CNS disorders. However DM is rapidly metabolized in humans. As a result, it is difficult to attain potential therapeutic blood levels of DM when it is dosed as a single agent. In addition to its activity at CNS receptors, the bupropion component of AXS 05 serves as a novel drug delivery method to inhibit DM metabolism and thereby increase its blood concentrations.
AXS-05 is currently in a Phase 3 trial for the treatment of treatment resistant depression (TRD), a Phase 2/3 trial for the treatment of agitation associated with Alzheimer’s Disease (AD) and a Phase 2 trial for the cessation of smoking.
An Independent Data Monitoring Committee (IDMC) conducted an interim analysis of the Phase 3 STRIDE-1 trial of AXS-05 in TRD in April 2018 and recommended that the study continue to full enrollment as well as indicating that AXS-05 appeared safe and well-tolerated.
Treatment Resistant Depression (TRD)
Patients diagnosed with major depressive disorder (MDD) are defined as having TRD if they have failed two or more antidepressant therapies. There are approximately 3 million estimated patients with TRD in the United States.
More about TRD
Agitation in Patient’s with Alzheimer’s Disease (AD)
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that manifests initially as forgetfulness advancing to severe cognitive impairment and memory loss. It is a common form of dementia and afflicts an estimated 5 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050. In addition to cognitive decline, individuals diagnosed with AD typically experience behavioral and psychological symptoms including agitation which is reported in approximately 45% of patients. Agitation is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition.
More about AD
The modulation of DM allows it to reach therapeutic plasma levels allowing DM to act on targeted CNS receptor systems. Combining the distinct and independent mechanisms of action of these two compounds with AXS-05 may be useful in the treatment of a variety of CNS disorders.


Marine life is amazing and it captivates ourselves with all its mysteries. Live unique sensations by seeing the most majestic cetaceans of the Mediterranean sea and the Atlantic Ocean. A 95% chance to spot some kind of cetacean! if not, you can come again for free!
The fabulous marine life
Come and discover the wonderful marine life of the Strait of Gibraltar. Whales, dolphins, killer whales ... you will experience unique sensations watching these majestic marine animals between the Mediterranean Sea and the Atlantic Ocean from our boats.
Departures are scheduled from the end of February to the beginning of November conditioned to the weather and will be made from the port of Tarifa (40 Km from Zahara de los Atunes)
We offer additional discounts for groups of more than 6 people.
|july and august||rest of months|
|adults||35 euros||30 euros|
|children (4 to 14 years old)||22 euros||20 euros|
|babies (1 to 3 years old)||10 euros||5 euros|
|babies (0 to 1 years old)||Free||Free|


Introduction to Postural Restoration
Postural Restoration evolved as a study of human biomechanics. This approach to healing is holistic and integrative. Clinically proven and scientifically based, Postural Restoration provides tools to evaluate underlying cause of pain, dysfunction and slow recovery from trauma. Treatment using Postural Restoration therapeutic activities has produced dramatic relief from chronic as well as acute conditions. These therapeutic activities reposition the musculoskeletal system, correct movement imbalance, restore normal tonicity to muscles and strengthen efficient, balanced, functional activity. Postural Restoration empowers you to maintain your optimal health and vitality in daily life and sports, and helps you avoid injury.
Postural Restoration recognized that humans are, by design, asymmetrical. Asymmetry facilitates our movement. Organ placement contributes to asymmetry. In the lower trunk the large, heavy liver is situated on the right while a smaller, lighter spleen is in a similar location on the left. Our right lung has three lobes, the left has only two, to accommodate the heart in our left upper trunk. The right diaphragm is larger and better positioned for respiration than the left diaphragm. Muscle attachments of the diaphragm to the ribs are thicker on the right. The right and left hemispheres of our brain govern different functions.
The majority of people worldwide are right handed. Our man made environment accommodates, even facilitates, right hand reach activity. The muscles that make up our right dominant movement patterns are used much more frequently and become much stronger than the same muscles of the non-dominant pattern. Even if you are left-handed you must live in a right-handed world.
Consequently, we all have the tendency to stand on our right leg and reach with our right arm. This reaching results in upper trunk rotation to the left. Consider how you open a door, reach for your cup, or brush your teeth. Often, people who are left-handed for fine motor activity use the right hand for power functions such as throwing. This dominant patterning is most useful! We don’t have to pause to consider which hand we will use to open the door. The pattern facilitates automatic activity, making life a bit simpler. Athletes thrive by strengthening powerful asymmetrical patterns. The downside of asymmetry is that our lifestyle – often sedentary and or filled with repetitive motion – reinforces our pattern so much that we can no longer move out of it. We lose the ability to balance our movement for example: to shift into our left hip and reach with the left hand. Although we walk with both legs, our center of gravity stays over the right hip. Although we have two lungs, we rely more heavily on the right. This one sided imbalance in activities that require alternate, reciprocal movement – such as walking, breathing and chewing – often results in abnormal stress, unequal wear and tear, dysfunction and pain.
As 3 dimensional beings, we function in 3 planes of motion: front to back – like taking a bow, side to side like climbing a ladder and in rotation as with twisting to see what’s behind us. Most healthy human movements take place in all three planes.
As asymmetric 3 dimensional beings, the spine orients to the right and we stand on the right leg. The upper trunk rotates back to the left in order to face straight ahead. In so doing right side bending occurs bringing the right ribs a bit closer to the right pelvis and the left ribs a bit further way from the left pelvis. In this position the right trunk muscles shorten and tighten, the left stretch and lengthen. The left abdominals thereby lose their optimal ability to anchor the left lower ribs and the left pelvic crest. The left pelvis rolls forward and inward, the left ribcage elevates and flares. In the front to back plane of motion there is excessive tightness of the back and overstretch of the abdominal regions. In the side-to-side plane of motion, structures on the right are generally too close together and structures on the left are generally too far apart. Finally, with these movement planes diminished, we have difficulty moving in a healthy way in the third plane of rotation at all. Each of these movement disorders can lead to unhealthy stress, chronic injury and pain.
In this 3 dimensional, asymmetric configuration the respiratory diaphragm (our primary muscle for inhalation) becomes poorly positioned for healthy breathing. Without efficient function of our primary, low energy breathing system, the diaphragm, we rely more heavily on our auxiliary, back up system- especially the helper muscles of the neck to get enough air into our body. Usually reserved for higher oxygen demand – as when we are running a marathon – the neck muscles become overactive, unable to relax. This activity triggers the sympathetic nervous system – our fight or flight, high alert system. In a constant state of stress, we are restless, unable to relax, unable to sleep deeply. I this vulnerable state, it does not take much to push us over the edge – whether physical, environmental, emotional or mental stress.
How Postural Restoration Can Help
The Postural Restoration therapist initiates a process of rehabilitation that begins with repositioning. Repositioning therapeutic activities are carefully constructed exercises to restore neutral alignment to the musculoskeletal system.
Results can be immediate or may take several sessions to achieve. Repositioning exercises incorporate breathing techniques to restore normal, efficient respiration. Repositioning exercises also teach the person how to feel the activation of corrective postural muscles.
Once neutral alignment is achieved, it must be maintained and integrated into the movement patterns we use in daily life activities. A personalized exercise program is designed to progress strengthening from lying to sitting to standing and finally back into upright movement in a more balanced way.
Often, the aches and pains and movement limitations previously experienced were the result of an imbalanced asymmetrical pattern. These pains drop away as more balanced, more efficient and less stressful muscle activity is restored. In some cases, true pathology may have developed, such as joint breakdown, muscle tears and adhesions and ligament strains. These will become evident and appropriate treatment can be more accurately determined and applied.
Postural Restoration techniques create a more balanced/less stressed physical foundation for life activities, sports activities and for rehabilitation following trauma or surgery. These techniques empower you to self maintain your optimum function and to enjoy an active life.


Our butterflies emerged from their chrysalids on Sunday. We missed witnessing the first few emerge, but were there to see the fourth one. Everyone gathered around to watch the butterfly crawl out and then crawl across the habitat. It didn't take very long before his wings had inflated.
You can see the newly emerged butterfly in the upper left corner of the photo below. Its wings are not yet inflated. You can also see the empty chrysalids.
Today, we released our butterflies in the front yard.
They obviously weren't bothered by their captivity. This we learned from their reluctance to leave the habitat. We had to bump the habitat a few times to get them to flutter around and find their way out.
One of the butterflies had a wing that had a deformity. We thought it might not be able to fly, but after a few minutes it flew off to go live its short butterfly life.


Nature Tourism in Kouga: Embrace the Beauty of the Wild
Welcome to Kouga, a nature lover’s haven just 80km from the bustling city of Gqeberha (formerly Port Elizabeth). Nestled in the adventure province, Kouga unfolds as a sanctuary of natural wonders, inviting you to explore, discover, and experience the rich tapestry of its landscapes.
Venture into pristine Nature Reserves like Cape St Francis, Jeffreys Bay, or the nearby Van Stadens Wild Flower Reserve, each a testament to the extraordinary plant and animal life that graces the Cape Floral Kingdom.
Traverse the winding rivers of Kouga, a water wonderland offering kayaking, scenic trails, and picturesque spots like the St Francis Bay Canals. Bird enthusiasts will find solace in the diverse habitats while wildlife reserves showcase the marine marvels of dolphins, Humpback and Southern Right Whales.
Embark on a journey through Kouga’s untouched beauty, where every reserve, river, and wildlife encounter promises an adventure of a lifetime.


Best known to be a ‘Zoo without Fences’, wildlife encounters are pretty much a given. Kangaroos, sea lions, koalas, echidnas, wallabies, goannas, and marine mammals are plentiful, along with many species of bird. If you are after wildlife, then Kangaroo Island will never disappoint.
- 3 nights at Grosvenor Hotel Adelaide ★★★★ in a Standard Room
- 3 nights at Mercure Kangaroo Island Lodge ★★★★ in a Superior Queen Poolview Room
- Morning pelican feeding sessions
- Self-guided nocturnal walk to spot wildlife and self-guided nature trails
- WiFi and parking
- Return ferry transfer from Cape Jervis to Penneshaw^ for car and passenger
- 4 days inclusive AVIS car hire in a Kia Rio or similar+


Karma cooked the goose.
Something got our male goose last night. I just realized that the gander was pacing the fence line all alone and when I went a-lookin', I found me a pile of feathers. No blood, no body or its parts; just nice white feathers.
We're not entirely sure what it is, but are starting to suspect a small coyote. We've been losing hens in the same way. I'd been thinking it might have been the eagles or the big hawks that have been around, but I think that the predator must be attacking on the ground, rather than in the air, because the male goose would have been more likely to stand up to the predator and attempt to protect both geese, thereby losing its life. With the water levels low right now, the fencing over the streams isn't good. Even the sheep have been sneaking through.
A coyote kills and plucks, and then takes the rest of the animal back to the den. This is consistent with what we are seeing.
I guess that enough time has passed since this goose attacked my child, because I'm feeling bad. I've been enjoying looking out at the pond and seeing the two of them sunning themselves. The male goose LOVED the water, and although he hadn't actually gone swimming, he would jump in and out of the sheep's water tub, splashing and flapping and then running like a lunatic around the field.
Also, as is the case in any death, I feel particularly sad for those who are left behind. Watching the gander right now is breaking my heart. I don't know how much we personify this experience for them, though, or what she is capable of thinking and feeling. But... the poor thing.
To sum it up.... when I called B.Rube at work to tell him, he ended our conversation with "That's Life on the Farm." Yep, I guess it is.


Cystoscopy is an endoscopic procedure where a tube is inserted into the urethra through the opening at the end of the penis. It allows me to visually examine the complete length of the urethra and the bladder for polyps, strictures, abnormal growths and other problems.
Why is the test is performed?
- To diagnose and evaluate disorders of the urinary tract
- To identify cancers of the bladder or urethra
- To determine the cause of pain in the urinary tract.
How does the test work?
There are two types of cystoscopes:
- Rigid cystoscope
- Flexible cystoscope
In both methods, the actual test is carried out very similarly, with the exception of the positioning. With the rigid cystoscope, you lie on your back with your knees up and apart. The penis and surrounding area is cleaned and local anesthetic jelly is placed into the urethra. The scope is then inserted through the urethra into the bladder. The flexible cystoscope does not require you to lie on your back with your knees up and apart for insertion. The choice of which scope to use depends on the purpose of the exam.
During the procedure, water is inserted through the cystoscope and into your bladder. When the bladder is full of water, it stretches. This allows a view of the entire bladder wall.
If any tissue appears abnormal, a biopsy can be taken through the cystoscope for analysis.
The entire procedure, including preparation, generally takes about 15 to 20 minutes. The examination portion of the procedure is generally less than five minutes.


Seeking a highly motivated postdoctoral fellow to join Dr. Loretta Li’s laboratory at Lurie Children’s Hospital / Northwestern University. We are a newly established translational leukemia research laboratory that uses a variety of biochemical, molecular, and cell biology approaches to identify new therapeutic targets, develop preclinical models of disease, and test novel therapeutics both in vitro and in vivo using mouse models. The successful candidate will be a team player capable of handling multiple tasks and adaptable to a fast-paced research environment.
Dr. Loretta Li Faculty Profile: https://www.luriechildrens.org/en/doctors/li-loretta-s/
The postdoctoral fellow will carry out an independent research project under the supervision of the principal investigator, Dr. Loretta Li. The successful candidate will be responsible for the following:
1. A level of knowledge normally acquired through the completion of a Ph.D. or M.D.
2. Possess an excellent command of the English language; medical and scientific terminology is required.
3. Organizational skills: Ability to establish priorities and react promptly to a large variety of requests and needs, sometimes in stressful situations.


Movement disorders can be a challenging condition to live with, affecting people of all ages. These disorders can affect your ability to move your body in a smooth and coordinated way, leading to symptoms such as tremors, stiffness, and difficulty walking. It's important to understand that movement disorders are not a personal weakness or character flaw - they are a medical condition that affects the way your brain controls movement.
In people with movement disorders, there are several changes that occur in the brain that can lead to symptoms such as tremors and stiffness. One of the key areas of the brain involved in movement disorders is the basal ganglia, which is responsible for controlling movement and coordinating muscle activity. In individuals with movement disorders, there may be a dysfunction in the basal ganglia, leading to abnormal movements and difficulty controlling muscle activity.
Another area of the brain that can be affected in people with movement disorders is the cerebellum, which is responsible for regulating balance and coordination. In individuals with movement disorders, there may be a malfunction in the cerebellum, leading to problems with balance and coordination.
It's important to remember that movement disorders can have a significant impact on your life, but there are many resources available to help you manage your symptoms and improve your quality of life. Treatment for movement disorders typically involves a combination of medication and physical therapy. Medications such as levodopa and dopamine agonists can help improve motor function, while physical therapy can help you maintain mobility and reduce the risk of falls.
Living with a movement disorder can be challenging, but it's important to remember that you are not alone. There are many support groups and organizations that can provide you with resources and support on your journey to managing your condition. With the right treatment and support, you can learn to manage your symptoms and live a fulfilling life, no matter what challenges you may face.


Does L’Oréal test on animals?
L’Oréal was able to end all animal testing for products as early as 1989, without making its products any less safe. This is thanks to its research & development of alternative methods to testing, particularly in the use of reconstructed skin models.
However, for some of its new ingredients, there’s still a small gap between what the replacement tests can help us predict about the ingredient and what we need to know to ensure its full safety, for example when predicting the ingredient’s potential for skin allergy. For these reasons, the Group still needs to resort to some animal testing, which today represents less than 1% of its safety assessments.
L’Oréal’s ambition is to replace the need for any animal testing, and the Group has already contributed to most of the replacement methods accepted today in the cosmetics industry, and continue to develop new ones.


STAY HOME. SAVE LIVES.
KEEP a Safe Distance
WASH Hand Often
COVER your cough
About Coronavirus Disease 2019
Coronaviruses are a large family of viruses that get their name from the halo of spiked proteins on their outer surface resembling a crown “the Corona” under a microscope. The new coronavirus is called SARS-CoV-2 which stands for Severe Acute Respiratory Syndrome Coronavirus 2. As a new virus, it means that previously no one in the world has been infected with it, and therefore, no one has antibodies to it. Because no one has an antibody everyone is at risk of catching, becoming ill, and spreading the virus. SARS-CoV-2(novel Coronavirus (Covid-19)) causes a disease called COVID-19, a severe respiratory illness. Covid-19 can be deadly, particularly for older people and those with underlying health conditions. It is passed from human to human.
The viruses spread through droplets in the air after coughing or sneezing, which people nearby can take in through their nose, mouth, or eyes. The viruses also spread by touching a contaminated surface. It is discovered that different types of materials have different persistence, mostly for from 2 hours up to 9 days. Also, it persists better at 50% compared to 30% relative humidity at room temperature. Lungs inside your body, the virus travels quickly to the back of your nasal passages and to the mucus membranes in the back of your throat. The virus attaches to a receptor called ACE-2 or Angiotensin-Converting Enzyme-2 on a respiratory cell in your body. The viruses’ genetic material enters your cell to produce copies of themselves, which go on to affect more cells.
The time between the initial infection and the first symptom appearing varies widely but is five days on average. Symptoms often start in the back of the throat, with a dry cough, sore throat along with fever. Symptoms become more severe as the infection starts making its way to your lower respiratory tract. Here, it can cause more respiratory problems like bronchitis and pneumonia. When the virus reaches your lung it causes inflammation in the air sacs in your lungs which are called alveoli, oxygen and carbon dioxide are exchanged.
In pneumonia there is swelling, decreased airflow, and alveoli start to be filled with fluid causing shortness of breath and difficulty in breathing. Some people need a ventilator to help a breath. Less oxygen in your blood deprives other major organs of oxygen including the liver, kidney, and brain. Acute respiratory distress caused by widespread swelling in the lungs stops the body from getting the oxygen it needs to survive. This respiratory distress can lead to organ failure and death.
Covid-19 can be deadly, the vast majority around 80% of cases are mild to moderate and people recover within a week or two.
Since the lockdowns have been transformed to unlock as a protocol to resume the economic activity of our country. With the availability of many services risk of spreading of Covid-19 has been increased. As it is said that prevention is better than cure, thus we must be careful and focus more on the prevention of this virus. To prevent the spread of Covid-19 here are a few points to follow while returning to the workplace or being at home:
- Put distance between yourself and others.
- Avoid close contact with sick people.
- Adopt flexible working hours.
- Avoid crowded public transport if possible go by bike or walk.
- If possible, discuss with your supervisor if you can work from home.
- Wear a mask when taking public transport.
- Cover coughs and sneezes with a disposable tissue or the inside of your elbow.
- Check body temperature when entering office buildings.
- Avoid crowded lifts as far as possible.
- At work or at home, if you can use the stairs instead of elevators.
- Avoid using your hands to touch common objects like elevator buttons, door handles, or staircase railings.
- Find no-contact ways to greet your colleagues and express affection to your friends and family.
- Avoid holding or joining large-scale meetings.
- Create distance-based meetings either through videoconferencing or by maintaining at least 1-meter space between people in the same room.
- Reduce face-to-face contact with co-workers.
- Arrange flexible meal hours.
- Avoid meal gatherings.
- Maintain good environmental hygiene at the workplace and wash hands frequently.
- After commuting t and from and throughout the day, clean your hands frequently and thoroughly.
- Avoid touching your eyes, mouth, and nose.
- After work, avoid crowed places or unnecessary activities.
- Ensure before leaving the house that all belongings are sanitized properly.
- If you feel unwell or even have a mild cough, don’t go to work, stay at home and avoid direct contact with anyone and seek prompt medical advice.
- Clean and disinfect tables, door handles, and other frequently touched surfaces.
- If possible keep the windows open and ventilate your workplace regularly.
- Remember to seek ways to stay active and positive.
- Stay healthy and let’s all prevent the spread of COVID-19!
Masks & Respirators
N95 masks & respirators
3-Ply and 2-Ply Masks
Latex Medical Examination Disposable
Instant Hand Sanitizer


It is an active, muscular, medium-sized dog of solid constitution. It appears full of strength, but not without distinction. It has sufficient substance and bone to bring good muscle, but it does not have to look heavy. His skull is broad and solid, with a marked stop; the snout is quite elongated and square in shape, with perfect teeth and developed nostrils. The eyes are hazel or brown; the ears are wide and long; the tail is medium long and slightly curved.


Wisdom Teeth Removal
Wisdom teeth, also known as third molars, are the last teeth in the jaws to develop. Typically, they develop in your late teens or early twenties. Wisdom teeth either come through the gums, called erupting, or they are blocked, which is called impaction. Impaction can vary in severity, from gum tissue blockage to complete bone coverage.
In most cases, we find that there is not enough room in the mouth for wisdom teeth to function properly and be easily cleaned, and extraction is recommended.
Impacted Wisdom Teeth
When wisdom teeth are impacted, problems with the jaw and adjacent teeth can develop. An impacted wisdom tooth can cause gum tissue infections, decay on the second molar, and possible crowding of other teeth. Serious problems can develop with infections spreading to the throat and neck, or cysts or tumors that can destroy jawbone to the point of fracture.
Evaluation and Removal
Dr. Greeff will evaluate your jaw structure and wisdom teeth status with regular oral exams and x-rays. In many cases, routine x-rays are not enough for a full evaluation of the wisdom teeth, jaw and surrounding structures. A panoramic x-ray is typically done, which allows for a complete assessment of the jaw and teeth.
When current or potential issues with the wisdom teeth are identified, early removal is recommended. Removing wisdom teeth at an earlier age can be easier, as the jawbone is less dense. In addition, if the teeth are removed before the root develops, it involves a less invasive procedure. Removal recommendations can be as early as age 12, or may be delayed until patients are in their later teens. Patients older than 30 typically have higher complication rates and lengthened healing time.


As lawns age or sustain heavy use from play, sports activities, pets, vehicle traffic and parking, soil compaction can result. Compaction greatly reduces the pore space within the soil that would normally hold air. Roots require oxygen to grow and absorb nutrients and water. Campaction has a negative impact on nutrient uptake and water infiltration, in addition to being a physical barrier to root growth. This results in poor top growth and lawn deterioration. Core aeration can benefit your lawn by:
- Increasing water, nutrient and oxygen movement into the soil.
- Enhancing infiltration of rainfall or irrigation.
- Improving rooting and plant resiliance.


A stated earlier, the presence of a Test lLine, no matter how faint, indicates the presence of SARS-CoV-2 antigen and thus a positive COVID-19 test result. But how able are rapid antigen tests to detect the presence of SARS-CoV-2 antigen?
The Liverpool School of Tropical Medicine evaluated the limit of detection of the Excalibur Rapid SARS-CoV-2 Antigen Test. In other words, to see how little antigen or live virus the test can detect.
SARS-CoV-2 N protein antigen was diluted from 500 pg/ml, representing a high level of antigen, through decreasing amounts down to 0 pg/ml, or no virus antigen present. Each dilution was applied to Excalibur Rapid SARS-CoV-2 Antigen Test cards and read by two observers, each blinded to the results of the other. A third observer was available to adjudicate discrepant tests.
The Excalibur test had 100% detection down to a level of 75 pg/ml, dropping to 30% at 50 pg/ml. Positive test results were seen down to 30 pg/ml.
Similar tests were carried out using live virus diluted down in stages from 10,000 plaque-forming units (PFUs)/ml to zero. Plaque forming units is a measure of the number of infectious virus particles per unit volume. The Excalibur test was able to detect 100% of replicates down to a level of 250 PFU/ml, dropping to 50% at 125 PFU/ml.
The Excalibur Rapid SARS-CoV-2 Antigen Test had a limit of detection of 250 PFU/ml, which exceeds the World Health Organisation recommendation of 500 PFU/ml.
There have been over 150 million confirmed cases of COVID-19 worldwide with new variants of the virus arising all the time. The most significant of these for the UK is the B.1.1.7 variant causing over 95% of new infections as of April 2021. It is therefore important to know if there is any reduction in sensitivity of currently available rapid antigen tests when exposed to the B.1.1.7 variant.
Researchers at the Liverpool School of Tropical Medicine have determined the limit of detection of several currently available rapid antigen tests1.
A clinically isolated SARS-CoV-2 strain from the B.1.1.7 lineage was serially diluted from 1,000,000 PFU/ml to 100 PFU/ml. Each dilution was tested in triplicate and applied to Excalibur Rapid SARS-CoV-2 Antigen Test cards and read by two observers, each blinded to the results of the other. A third observer was available to adjudicate discrepant tests. The limit of detection was defined as the lowest dilution at which all three replicates were deemed to be positive.
The Excalibur Rapid SARS-CoV-2 Antigen Test had a limit of detection of ≤ 500 PFU/ml, meeting or exceeding the British Department of Health and Social Care (DHSC) acceptable criteria.
Similar tests performed using the B.1 2020 strain taken from previously published work show the Excalibur Rapid SARS-CoV-2 Antigen Test to have a limit of detection of 250 PFU/ml.
This study demonstrates equivalent performance with SARS-CoV-2 B.1.1.7 as with the original dominant strain from the beginning of the pandemic.
Reference: 1. Kontogianni K, Cubas-Atienzar AI, Wooding D et al. Liverpool School of Tropical Medicine 2021. Unpublished.
For further information click here.


PROTECTING LIFE ON EARTH
Our commitment to defending endangered animal species
Stories of hope, resilience, and the wonders of the natural world. Through a captivating collection of spectacular images, we shine a spotlight on endangered animal species that are, slowly but surely, on the path to recovery. This remarkable achievement is made possible by the protected havens meticulously monitored by the COSMO-SkyMed satellites, illustrating the power of conservation efforts and the enduring spirit of nature.
The International Union for Conservation of Nature has become the global organisation and authority on the status of the natural world and the measures needed to safeguard it. In collaboration with the Italian IUCN Committee, the National network of members of the IUCN, we explore the journey of these extraordinary creatures, which, despite the persistent risk, represent the possibility of a brighter future.
The LOVE PLANET EARTH 2024 calendar, with its breathtaking imagery, serves as a powerful testament to the vital mission of COSMO-SkyMed in safeguarding these precious natural areas. Through these captivating visuals, it underlines our deep commitment to the preservation of Earth’s incredible biodiversity. It signifies our collective dedication to fostering a sustainable future, where the wonders of the natural world continue to thrive, offering hope, resilience, and inspiration to all living beings.
On the top: Vaquitas were last assessed for the IUCN Red List of ThreatenedSpecies in 2022. Phocoena sinusis listed as Critically Endangered. The total population is thought to be approximately 10 specimens, so clearly the number of mature individuals is far fewer than 250; this species is still declining and all mature individuals are in one population.
|Established in 1964, the Red List of Threatened Species of the IUCN (International Union for Conservation of Nature) is the world’s most comprehensive information source on the global conservation status of fungi, animal and plant species. The IUCN Red List is a critical indicator of the health of the world’s biodiversity. It is a powerful tool to inform and catalyse action for biodiversity conservation and policy change, critical to protecting the natural resources we need to survive. The IUCN Red List Categories are meant to be a system for easily classifying species at risk of global extinction.
It assesses and evaluates species and divides them into nine categories:
Not Evaluated (NE), Data Deficient (DD), Least Concern (LC), Near Threatened (NT), Vulnerable (VU), Endangered (EN),Critically Endangered (CR), Extinct in the Wild (EW) and Extinct (EX).


You probably know that your mouth is home to one of the largest populations of bacteria in your body. While they’re an independent bunch, you can dramatically influence their effect on your health. It starts with understanding how the key bacterial players operate and your role in altering their destructive tendencies.
Your teeth and the surrounding jaw muscles present a powerhouse capable of crushing even the hardest foods to pieces. But sometimes we use our teeth in ways that push them to the limit and lead to unnecessary problems and treatment. Learn about one habit that may accelerate the breakdown of your teeth and how to read the symptoms your teeth share with you.
When you wake up in the morning, no one expects your breath to smell very good. With a few good hygiene habits, your breath is usually ready for the day. But if you’re struggling with bad breath, or you suspect it might be a problem, we have a few tips to kick this social issue to the curb. Learn more here about the real causes and how to keep your breath fresh every day.


Healthy turf: basis for higher sporting performances
On turf of higher quality athletes perform better. An optimal management of your sports fields requires insight into all aspects that influence the health of the grass: soil, plant and water. Analyzing the soil, plant and water provide indispensable information. Knowledge aboutthe top layer, the health of the turf and the quality of the irrigation water influences the outcome of your maintenance plan and avoids unexpected maintenance costs afterwards.
The top layer forms the basis of every playing field. Every fieldmanager recognizes the importance of an optimal soil structure. However, this is easier said than done. After all, a good structure is determined by the optimal balance between a large number of factors: air, water, food, organic matter and soil life.
Fertilization Monitor Sport is a complete analysis that provides insight into the most important soil-aspects: the nutrients, pH, CEC, the organic matter content, soil texture, pF-curve et cetera. De Fertilization Monitor Sport is a thorough analysis with which you can further optimize your maintenance plan.
A healthy soil protects plants from diseases. But plants can also become ill in healthy soils. If you detect fungi or diseases in the grass you want to know what the cause is. Only then a proper treatment is possible and you can limit the risk of spreading. However, cause and consequence of certain symptoms are sometimes difficult to distinguish. Apart from fungi and bacteria other stress factors like nematodes can also affect the plant health.
DNA Multiscan provides insight into the presence of pathogens in turf even before giving visual damage. The DNA Multiscan is a unique DNA technique that quickly and reliably demonstrates the presence of fungi in the turf. This allows you to detect the presence of fungi at an early stage and to take the right measures in time.
Nematodes analyse provides information about more than 25 relevant nematode species.
Irrigation in the dry summer months is of great importance to prevent dehydration. In practice however irrigation water can cause many growth problems in the turf if the water contains too high levels of iron (Fe), sodium carbonate and other forms of salt!


I walk the dog early every morning before work, which means we see a lot of wildlife. Mostly we come across deer, turkeys, porcupines, squirrels and birds, but on Thursday morning, we came across seven turtles, which means it is nesting time!
They mostly nest in sandy soil in the sunshine, which means the sand pit that we walk by is ideal for them.
Although the dog was really well behaved and listened to me and left the turtles alone, I think we will be avoiding that trail for the next little while to let the turtles do their thing in peace.
Be careful driving too as many turtles are crossing roads to get to nesting ground!


Buck Moth Spraying Registration Form
Our prices are $190 first tree and $90 each additional.
The buck moth is a common insect found in oak trees, stretching in the United States from peninsular Florida to New England, and as far west as Texas and Kansas. The larvae typically emerge in a single generation in the spring.The larvae are covered in hollow spines that are attached to a poison sac. The poison can cause symptoms ranging from stinging, itching and burning sensations to nausea. The larvae feed on various oaks including scrub oak, live oak, blackjack oak, white oak, and dwarf chinquapin oak.
Eggs are typically laid in spiral clusters on oak twigs. Mature larvae enter the soil or leaf litter to pupate in late July and emerge between October and the following February as moths to mate and lay eggs. In Louisiana where use of live oaks as street trees is extensive, the caterpillars can become a significant nuisance for humans. With proper treatment the risk of this nuisance can be reduced. Trees can not be sprayed until caterpillars have hatched.
Please fill out the form below and return to us to register for our buckmoth spraying services. The first tree to be treated is $190 with each additional tree treated at the same time is $90. Treatments will be scheduled first contact first scheduled. We will call to schedule so that animals can be put away and other precautions needed can be addressed. Don't take the RISK of being stung register today!


(Source: Science Media Centre) –
AstraZeneca has published a press release announcing that the Oxford-AstraZeneca COVID-19 vaccine US Phase III trial met primary efficacy endpoint in preventing COVID-19 at interim analysis.
Dr Andrew Garrett, Executive VP, Scientific Operations, ICON Clinical Research, said:
“This is clearly stated as an AstraZeneca-led trial, and it more closely follows the large phase III vaccine trials reported by other sponsors. In this respect it is a solid 30,000 plus participant study with a placebo control, and a simple 4 week dosing interval, such that interpretation is more straightforward than previous Oxford/AZ vaccine trials. It has a good age mix with more than 6,000 participants aged >65 years and also wide ethnic representation. Interim efficacy is clearly stated as being 79% against symptomatic COVID-19 and 100% effective against severe disease. Detailed numbers are not provided at this time and the lower confidence limit is not stated. Importantly the trial provides further support for efficacy in the elderly (80%) where previous clinical trial data, other than immunological data, had been lacking. The study randomized two subjects to receive vaccine for every subject that received placebo providing a large safety database of 20,000 plus participants who received active vaccine. As described, this has been used to investigate the potential association of the vaccine with thrombotic events and specifically cerebral venous sinus thrombosis, of which there were no cases detected. Overall it was reported that there was no increased risk of thrombosis. These data are therefore timely in further addressing any safety concerns that could undermine vaccine uptake.
“The trial is directed at generating data to support emergency use in the US but also provides valuable data to other countries – both confirming efficacy using a 4-week dosing interval and re-enforcing vaccine safety.”
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“These results are not surprising given what we know now. The US regulatory authorities are reluctant, even in a pandemic, to rely totally on data obtained outside the US, so this trial was done to provide convincing evidence of efficacy and safety in a sufficiently large number of US patients. The benefits of these results will mainly be for the rest of the world where confidence in the AZ vaccine has been eroded, largely by political and media comment. Once that happens, reporting of adverse effects becomes very biased and confidence can spiral downwards. The rest of the world that will rely on this low-cost vaccine may be able to procced with vaccinating their populations.
“Vaccine development and rollout should be an international collaboration rather than nationalistic fervour whether in favour of, or against, a particular vaccine. Assessment should be based on science alone.
“It is important also to realise that the “headline” efficacy numbers are valid for comparison between the groups in a trial, but great care is needed in comparisons between trials. The way that events are assessed and counted as well as the context of a trial means that exact values for any between trial comparison are uncertain, not only because of statistical uncertainty, but also because of these other factors.
“It is clear this vaccine has very good efficacy (remember that 60% was, prior to any trials being started, regarded as a good target), and that this efficacy does not show a notable decline at older ages. This was expected and the speculation that it was ineffective (or “quasi-ineffective”) at older ages was totally unjustified.
“This is good news for the global community and one hopes that any political statements around this good news are avoided.”
University of Oxford press release: https://www.ovg.ox.ac.uk/news/usa-chile-and-peru-interim-trial-data-show-oxford-astrazeneca-vaccine-is-safe-and-highly-effective
All our previous output on this subject can be seen at this weblink:www.sciencemediacentre.org/tag/covid-19
Dr Andrew Garrett: “I am employed by ICON which is a Contract Research Organization. ICON provides pharmaceutical services to the pharmaceutical and biotechnology industries. ICON conducts clinical trials on behalf of Sponsors, including vaccine trials. I am a member of the UK Statistical Authority’s (UKSA) Research Accreditation Panel. I have received one dose of the Oxford/AstraZeneca vaccine as part of the UK vaccination program.”
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs. I am a participant in the Oxford/Astra Zeneca trial, and on 13th January 2021 learnt I had received the active vaccine.”


Coffee is a brewed drink prepared from roasted coffee beans, which are the seeds of berries from the Coffea plant. The genus Coffea is native to tropical Africa (specifically having its origin in Ethiopia and Sudan) and Madagascar, the Comoros, Mauritius, and Réunion in the Indian Ocean. The plant was exported from Africa to countries around the world.
“Even bad coffee is better than no coffee at all.”
Coffee is slightly acidic and has a stimulating effect on humans because of its caffeine content. Coffee is one of the most popular drinks in the world.It can be prepared and presented in a variety of ways (e.g., espresso, French press, café latte, etc.). It is usually served hot, although iced coffee is a popular alternative.
Clinical studies indicate that moderate coffee consumption is benign or mildly beneficial in healthy adults, with continuing research on whether long-term consumption lowers the risk of some diseases, although there is generally poor quality of such studies.
The earliest credible evidence of coffee-drinking appears in Yemen in southern Arabia in the middle of the 15th century in Sufi shrines. It was here in Arabia that coffee seeds were first roasted and brewed in a similar way to how it is now prepared.
Coffee seeds were first exported from East Africa to Yemen, as the coffea arabica plant is thought to have been indigenous to the former. Yemeni traders took coffee back to their homeland and began to cultivate the seed. By the 16th century, it had reached Persia, Turkey, and North Africa. From there, it spread to Europe and the rest of the world.