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95-422: Sphingomyelin was first isolated by German chemist Johann L.W. Thudicum in the 1880s. The structure of sphingomyelin was first reported in 1927 as N-acyl-sphingosine-1-phosphorylcholine. Sphingomyelin content in mammals ranges from 2 to 15% in most tissues, with higher concentrations found in nerve tissues, red blood cells, and the ocular lenses. Sphingomyelin has significant structural and functional roles in

190-404: A ceramide. This composition allows sphingomyelin to play significant roles in signaling pathways: the degradation and synthesis of sphingomyelin produce important second messengers for signal transduction. Sphingomyelin obtained from natural sources, such as eggs or bovine brain, contains fatty acids of various chain length. Sphingomyelin with set chain length, such as palmitoylsphingomyelin with

285-503: A deficiency in the lysosomal enzyme acid sphingomyelinase , which causes the accumulation of sphingomyelin in spleen , liver , lungs , bone marrow , and brain , causing irreversible neurological damage. Of the two types involving sphingomyelinase , type A occurs in infants. It is characterized by jaundice , an enlarged liver, and profound brain damage. Children with this type rarely live beyond 18 months. Type B involves an enlarged liver and spleen, which usually occurs in

380-477: A lipid matrix, like "bricks and mortar." Together with cholesterol and free fatty acids, ceramides form the lipid mortar, a water-impermeable barrier that prevents evaporative water loss. As a rule of thumb, the epidermal lipid matrix is composed of an equimolar mixture of ceramides (~50% by weight), cholesterol (~ 25% by weight), and free fatty acids (~15% by weight), with smaller quantities of other lipids also being present. The lipid barrier also protects against

475-399: A number of apoptotic agents, including ionizing radiation, UV light, TNF-alpha , and chemotherapeutic agents . This suggests a role for ceramide in the biological responses of all these agents. Because of its apoptosis-inducing effects in cancer cells, ceramide has been termed the "tumor suppressor lipid". Several studies have attempted to define further the specific role of ceramide in

570-431: A number of pathological states including cancer , neurodegeneration , diabetes , microbial pathogenesis, obesity , and inflammation . Several distinct ceramides potently predict major adverse cardiovascular events (MACE), namely C16:0, C18:0, and C24:1, although C24:0 has an inverse relationship. C16-C18 are harmful in the liver. Ceramide levels are positively correlated with inflammation and oxidative stress in

665-499: A result of impaired mitochondrial fatty acid synthesis (mtFAS). For example, while the concentration of sphingomyelin is noticeably increased, the concentration of ceramides is proportionally decreased. Ceramides may be found as ingredients of some topical skin medications used to complement treatment for skin conditions such as eczema . They are also used in cosmetic products such as some soaps, shampoos, skin creams, and sunscreens. Additionally, ceramides are being explored as

760-437: A result of saturated fat activation of TLR4 receptors. Unsaturated fat does not have this effect. Ceramides induce insulin resistance in many tissues by inhibition of Akt/PKB signaling . Aggregation of LDL cholesterol by ceramide causes LDL retention in arterial walls, leading to atherosclerosis . Ceramides cause endothelial dysfunction by activating protein phosphatase 2 (PP2A). In mitochondria, ceramide suppresses

855-418: A saturated 16 acyl chain, is available commercially. Ideally, sphingomyelin molecules are shaped like a cylinder, however many molecules of sphingomyelin have a significant chain mismatch (the lengths of the two hydrophobic chains are significantly different). The hydrophobic chains of sphingomyelin tend to be much more saturated than other phospholipids. The main transition phase temperature of sphingomyelins

950-505: A shared descent, culture, and history. Völkisch elements identified Germanness with "a shared Christian heritage" and "biological essence", to the exclusion of the notable Jewish minority. After the Holocaust and the downfall of Nazism, "any confident sense of Germanness had become suspect, if not impossible". East Germany and West Germany both sought to build up an identity on historical or ideological lines, distancing themselves both from

1045-437: A significant role in the phase of sphingomyelin. Sphingomyelin are also more prone to intermolecular hydrogen bonding than other phospholipids. Sphingomyelin is synthesized at the endoplasmic reticulum (ER), where it can be found in low amounts, and at the trans Golgi. It is enriched at the plasma membrane with a greater concentration on the outer than the inner leaflet. The Golgi complex represents an intermediate between

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1140-475: A substantial German population. Following the end of World War I , Austria-Hungary and the German Empire were partitioned, resulting in many Germans becoming ethnic minorities in newly established countries. In the chaotic years that followed, Adolf Hitler became the dictator of Nazi Germany and embarked on a genocidal campaign to unify all Germans under his leadership. His Nazi movement defined Germans in

1235-578: A substantial additional number of Germans were in the multiethnic kingdom of Austria-Hungary . During this time, a large number of Germans also emigrated to the New World , particularly to the United States , especially to present-day Pennsylvania . Large numbers also emigrated to Canada and Brazil , and they established sizable communities in New Zealand and Australia . The Russian Empire also included

1330-461: A very specific way which included Austrians , Luxembourgers , eastern Belgians , and so-called Volksdeutsche , who were ethnic Germans elsewhere in Europe and globally. However, this Nazi conception expressly excluded German citizens of Jewish or Roma background. Nazi policies of military aggression and its persecution of those deemed non-Germans in the Holocaust led to World War II in which

1425-550: Is a component of vernix caseosa , the waxy or cheese-like white substance found coating the skin of newborn human infants. There are three major pathways of ceramide generation. First, the sphingomyelinase pathway uses an enzyme to break down sphingomyelin in the cell membrane and release ceramide. Second, the de novo pathway creates ceramide from less complex molecules. Third, in the "salvage" pathway, sphingolipids that are broken down into sphingosine are reused by reacylation to form ceramide. Hydrolysis of sphingomyelin

1520-408: Is a lipid-soluble second messenger that can pass along a signal cascade. In addition, the degradation of sphingomyelin can produce ceramide which is involved in the apoptotic signaling pathway. Sphingomyelin has been found to have a role in cell apoptosis by hydrolyzing into ceramide . Studies in the late 1990s had found that ceramide was produced in a variety of conditions leading to apoptosis. It

1615-481: Is also higher compared to the phase transition temperature of similar phospholipids, near 37 °C. This can introduce lateral heterogeneity in the membrane, generating domains in the membrane bilayer. Sphingomyelin undergoes significant interactions with cholesterol. Cholesterol has the ability to eliminate the liquid to solid phase transition in phospholipids. Due to sphingomyelin transition temperature being within physiological temperature ranges, cholesterol can play

1710-605: Is an important part of German culture, particularly in Southern Germany and the Rhineland . An important German festival is the Oktoberfest . A steadily shrinking majority of Germans are Christians . About a third are Roman Catholics , while one third adheres to Protestantism . Another third does not profess any religion. Christian holidays such as Christmas and Easter are celebrated by many Germans. The number of Muslims

1805-579: Is based on High German and Central German , and is the first or second language of most Germans, but notably not the Volga Germans . Low German , which is often considered to be a distinct language from both German and Dutch, was the historical language of most of northern Germany, and is still spoken by many Germans, often as a second language. It is estimated that there are over 100 million Germans today, most of whom live in Germany, where they constitute

1900-410: Is catalyzed by the enzyme sphingomyelinase . Because sphingomyelin is one of the four common phospholipids found in the plasma membrane of cells, the implications of this method of generating ceramide is that the cellular membrane is the target of extracellular signals leading to programmed cell death. There has been research suggesting that when ionizing radiation causes apoptosis in some cells,

1995-566: Is considered a defining moment in German history. While the Romans were nevertheless victorious, rather than installing a Roman administration they controlled the region indirectly for centuries, recruiting soldiers there, and playing the tribes off against each other. The early Germanic peoples were later famously described in more detail in Germania by the 1st century Roman historian Tacitus . At this time,

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2090-505: Is growing. There is also a notable Jewish community, which was decimated in the Holocaust . Remembering the Holocaust is an important part of German culture. A German ethnic identity began to emerge during the early medieval period . These peoples came to be referred to by the High German term diutisc , which means "ethnic" or "relating to the people". The German endonym Deutsche is derived from this word. In subsequent centuries,

2185-535: Is now Germany, west of the Rhine river. He specifically noted the potential future threat which could come from the related Germanic peoples ( Germani ) east of the river. Archaeological evidence shows that at the time of Caesar's invasion, both Gaul and Germanic regions had long been strongly influenced by the celtic La Tène culture . However, the Germanic languages associated with later Germanic peoples were approaching

2280-499: Is particularly rich in sphingomyelin, suggesting its role as an insulator of nerve fibers. The plasma membrane of other cells is also abundant in sphingomyelin, though it is largely to be found in the exoplasmic leaflet of the cell membrane. There is, however, some evidence that there may also be a sphingomyelin pool in the inner leaflet of the membrane. Moreover, neutral sphingomyelinase-2 – an enzyme that breaks down sphingomyelin into ceramide – has been found to localise exclusively to

2375-463: Is produced as a byproduct when the phosphocholine is transferred. Sphingomyelin breakdown is responsible for initiating many universal signaling pathways. It is hydrolyzed by sphingomyelinases (sphingomyelin specific type-C phospholipases). The phosphocholine head group is released into the aqueous environment while the ceramide diffuses through the membrane. The membranous myelin sheath that surrounds and electrically insulates many nerve cell axons

2470-475: Is reduced, yielding dihydrosphingosine. The dihydrosphingosine undergoes N-acylation followed by desaturation to yield a ceramide. Each one of these reactions occurs at the cytosolic surface of the endoplasmic reticulum . The ceramide is transported to the Golgi apparatus where it can be converted to sphingomyelin. Sphingomyelin synthase is responsible for the production of sphingomyelin from ceramide. Diacylglycerol

2565-602: Is then followed by acylation by the enzyme (dihydro)ceramide synthase to produce dihydroceramide . The final reaction to produce ceramide is catalyzed by dihydroceramide desaturase . De novo synthesis of ceramide occurs in the endoplasmic reticulum . Ceramide is subsequently transported to the Golgi apparatus by either vesicular trafficking or the ceramide transfer protein CERT. Once in the Golgi apparatus, ceramide can be further metabolized to other sphingolipids , such as sphingomyelin and

2660-616: The Cold War , but were reunified in 1990. Although there were fears that the reunified Germany might resume nationalist politics, the country is today widely regarded as a "stablizing actor in the heart of Europe" and a "promoter of democratic integration". German is the native language of most Germans. It is the key marker of German ethnic identity. German is a West Germanic language closely related to Frisian (in particular North Frisian and Saterland Frisian ), Luxembourgish , English , Dutch , and Low German . Modern Standard German

2755-725: The Congress of Vienna (1815), and left most of the German states loosely united under the German Confederation . The confederation came to be dominated by the Catholic Austrian Empire , to the dismay of many German nationalists, who saw the German Confederation as an inadequate answer to the German Question . Throughout the 19th century, Prussia continued to grow in power. In 1848 , German revolutionaries set up

2850-602: The Kingdom of Poland , where they came to constitute a significant proportion of the population in many urban centers such as Gdańsk . During the 13th century, the Teutonic Knights began conquering the Old Prussians , and established what would eventually become the powerful German state of Prussia . Further south, Bohemia and Hungary developed as kingdoms with their own non-German speaking elites. The Austrian March on

2945-690: The Middle Danube stopped expanding eastwards towards Hungary in the 11th century. Under Ottokar II , Bohemia (corresponding roughly to modern Czechia) became a kingdom within the empire, and even managed to take control of Austria, which was German-speaking. However, the late 13th century saw the election of Rudolf I of the House of Habsburg to the imperial throne, and he was able to acquire Austria for his own family. The Habsburgs would continue to play an important role in European history for centuries afterwards. Under

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3040-518: The Romantic era saw a notable flourishing of German culture. Germans of this period who contributed significantly to the arts and sciences include the writers Johann Wolfgang von Goethe , Friedrich Schiller , Johann Gottfried Herder , Friedrich Hölderlin , E. T. A. Hoffmann , Heinrich Heine , Novalis and the Brothers Grimm , the philosopher Immanuel Kant , the architect Karl Friedrich Schinkel ,

3135-441: The electron transport chain and induces production of reactive oxygen species . One of the most studied roles of ceramide pertains to its function as a proapoptotic molecule. Apoptosis , or Type I programmed cell death , is essential for the maintenance of normal cellular homeostasis and is an important physiological response to many forms of cellular stress. Ceramide accumulation has been found following treatment of cells with

3230-542: The hyperplastic disorder psoriasis , investigators have reported an increase in AS and NS ceramides and a decrease in EOS, AP, and NP ceramides, which may contribute to a defect in the skin's water impermeability barrier. Studying ceramide expression in atopic dermatitis and psoriasis patients, other investigators have reported that rather than focusing on ceramide classes, ceramide sphingoid base length and fatty acid chain length have

3325-484: The red blood cell plasma membrane . This results in abnormally shaped red cells called acanthocytes . Germans Germans ( German : Deutsche , pronounced [ˈdɔʏtʃə] ) are the natives or inhabitants of Germany , or sometimes more broadly any people who are of German descent or native speakers of the German language . The constitution of Germany , implemented in 1949 following

3420-573: The "humiliation of Versailles", continuing traditions of authoritarian and antisemitic ideologies, and the Great Depression all contributed to the rise of Austrian-born Adolf Hitler and the Nazis, who after coming to power democratically in the early 1930s, abolished the Weimar Republic and formed the totalitarian Third Reich . In his quest to subjugate Europe, six million Jews were murdered in

3515-464: The ER and plasma membrane, with slightly higher concentrations towards the trans side. The synthesis of sphingomyelin involves the enzymatic transfer of a phosphocholine from phosphatidylcholine to a ceramide. The first committed step of sphingomyelin synthesis involves the condensation of L-serine and palmitoyl-CoA . This reaction is catalyzed by serine palmitoyltransferase . The product of this reaction

3610-700: The German inventor Johannes Gutenberg contributed to the formation of a new understanding of faith and reason. At this time, the German monk Martin Luther pushed for reforms within the Catholic Church. Luther's efforts culminated in the Protestant Reformation . Religious schism was a leading cause of the Thirty Years' War , a conflict that tore apart the Holy Roman Empire and its neighbours, leading to

3705-506: The German lands were relatively decentralized, leading to the maintenance of a number of strong regional identities. The German nationalist movement emerged among German intellectuals in the late 18th century. They saw the Germans as a people united by language and advocated the unification of all Germans into a single nation state, which was partially achieved in 1871. By the late 19th and early 20th century, German identity came to be defined by

3800-467: The German lands. The Habsburg dynasty managed to maintain their grip upon the imperial throne in the early modern period . While the empire itself continued to be largely de-centralized, the Habsburgs own personal power increased outside of the core German lands. Charles V personally inherited control of the kingdoms of Hungary and Bohemia, the wealthy low countries (roughly modern Belgium, Luxembourg and

3895-752: The German states, including the German emperor Wilhelm II , were overthrown in the November Revolution which led to the establishment of the Weimar Republic . The Germans of the Austrian side of the Dual Monarchy proclaimed the Republic of German-Austria , and sought to be incorporated into the German state, but this was forbidden by the Treaty of Versailles and Treaty of Saint-Germain . What many Germans saw as

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3990-622: The Germanic peoples, or Germani , were fragmented into a large number of peoples who were frequently in conflict with both the Roman Empire and one another. He described them as a diverse group, dominating a much larger area than Germany, stretching to the Vistula in the east, and Scandinavia in the north. German ethnicity began to emerge in medieval times among the descendants of those Germanic peoples who had lived under heavy Roman influence between

4085-409: The Germans have been represented by many prominent personalities in a significant number of disciplines, including Nobel prize laureates where Germany is ranked third among countries of the world in the number of total recipients. The English term Germans is derived from the ethnonym Germani , which was used for Germanic peoples in ancient times. Since the early modern period, it has been

4180-428: The Germans. By the late 18th century, German intellectuals such as Johann Gottfried Herder articulated the concept of a German identity rooted in language, and this notion helped spark the German nationalist movement, which sought to unify the Germans into a single nation state . Eventually, shared ancestry, culture and language (though not religion) came to define German nationalism. The Napoleonic Wars ended with

4275-449: The Holocaust . WWII resulted in widespread destruction and the deaths of tens of millions of soldiers and civilians, while the German state was partitioned. About 12 million Germans had to flee or were expelled from Eastern Europe. Significant damage was also done to the German reputation and identity, which became far less nationalistic than it previously was. The German states of West Germany and East Germany became focal points of

4370-682: The Jastorf Culture, but it is unclear whether these indicate ethnic continuity. Under Caesar's successors, the Romans began to conquer and control the entire region between the Rhine and the Elbe which centuries later constituted the largest part of medieval Germany. These efforts were significantly hampered by the victory of a local alliance led by Arminius at the Battle of the Teutoburg Forest in 9 AD, which

4465-662: The Middle Ages, and competed with the nobility for power. Between the 11th and 13th centuries, Germans actively participated in five Crusades to "liberate" the Holy Land . From the beginnings of the kingdom, its dynasties also participated in a push eastwards into Slavic-speaking regions. At the Saxon Eastern March in the north, the Polabian Slavs east of the Elbe were conquered over generations of often brutal conflict. Under

4560-447: The Nazi past and each other. After German reunification in 1990, the political discourse was characterized by the idea of a "shared, ethnoculturally defined Germanness", and the general climate became increasingly xenophobic during the 1990s. Today, discussion on Germanness may stress various aspects, such as commitment to pluralism and the German constitution ( constitutional patriotism ), or

4655-770: The Nazi regime was defeated by allied powers , led by the United States , the United Kingdom , and the former Soviet Union . In the aftermath of Germany's defeat in the war, the country was occupied and once again partitioned. Millions of Germans were expelled from Central and Eastern Europe. In 1990, West Germany and East Germany were reunified . In modern times, remembrance of the Holocaust, known as Erinnerungskultur ("culture of remembrance"), has become an integral part of German identity. Owing to their long history of political fragmentation, Germans are culturally diverse and often have strong regional identities. Arts and sciences are an integral part of German culture , and

4750-675: The Netherlands), the Kingdoms of Castile, Aragon, Sicily, Naples, and Sardinia, and the Dukedom of Milan. Of these, the Bohemian and Hungarian titles remained connected to the imperial throne for centuries, making Austria a powerful multilingual empire in its own right. On the other hand, the low countries went to the Spanish crown and continued to evolve separately from Germany. The introduction of printing by

4845-460: The Rhine and Elbe rivers. This included Franks , Frisians , Saxons , Thuringii , Alemanni and Baiuvarii - all of whom spoke related dialects of West Germanic . These peoples had come under the dominance of the western Franks starting with Clovis I , who established control of the Romanized and Frankish population of Gaul in the 5th century, and began a process of conquering the peoples east of

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4940-618: The Rhine area since at least the 2nd century BC. The resulting demographic situation reported by Caesar was that migrating Celts and Germanic peoples were moving into areas which threatened the Alpine regions and the Romans. The modern German language is a descendant of the Germanic languages which spread during the Iron Age and Roman era. Scholars generally agree that it is possible to speak of Germanic languages existing as early as 500 BCE. These Germanic languages are believed to have dispersed towards

5035-529: The Rhine from the direction of the Jastorf culture , which was itself a Celtic influenced culture that existed in the Pre-Roman Iron Age , in the region near the Elbe river. It is likely that first Germanic consonant shift , which defines the Germanic language family, occurred during this period. The earlier Nordic Bronze Age of southern Scandinavia also shows definite population and material continuities with

5130-641: The Rhine. The regions long continued to be divided into " Stem duchies ", corresponding to the old ethnic designations. By the early 9th century AD, large parts of Europe were united under the rule of the Frankish leader Charlemagne , who expanded the Frankish empire in several directions including east of the Rhine, consolidating power over the Saxons and Frisians , and establishing the Carolingian Empire . Charlemagne

5225-607: The action of ceramide synthase. Thus, ceramide synthase family members probably trap free sphingosine released from the lysosome at the surface of the endoplasmic reticulum or in endoplasmic reticulum-associated membranes. The salvage pathway has been estimated to contribute from 50% to 90% of sphingolipid biosynthesis. As a bioactive lipid, ceramide has been implicated in a variety of physiological functions including apoptosis , cell growth arrest, differentiation, cell senescence , cell migration and adhesion. Roles for ceramide and its downstream metabolites have also been suggested in

5320-646: The arts and crafts. In the late Middle Ages the German economy grew under the influence of urban centers, which increased in size and wealth and formed powerful leagues, such as the Hanseatic League and the Swabian League , in order to protect their interests, often through supporting the German kings in their struggles with the nobility. These urban leagues significantly contributed to the development of German commerce and banking. German merchants of Hanseatic cities settled in cities throughout Northern Europe beyond

5415-421: The cell. It is a plasma membrane component and participates in many signaling pathways. The metabolism of sphingomyelin creates many products that play significant roles in the cell. Sphingomyelin consists of a phosphocholine head group, a sphingosine , and a fatty acid . It is one of the few membrane phospholipids not synthesized from glycerol. The sphingosine and fatty acid can collectively be categorized as

5510-403: The cerebrospinal fluid, particularly tumor necrosis factor alpha . This activates sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide; sphingomyelinase activity has been observed in conjunction with cellular apoptosis. An excess of sphingomyelin in the red blood cell membrane (as in abetalipoproteinemia ) causes excess lipid accumulation in the outer leaflet of

5605-421: The complex glycosphingolipids . Constitutive degradation of sphingolipids and glycosphingolipids takes place in the acidic subcellular compartments, the late endosomes and the lysosomes , with the end goal of producing sphingosine. In the case of glycosphingolipids, exohydrolases acting at acidic pH optima cause the stepwise release of monosaccharide units from the end of the oligosaccharide chains, leaving just

5700-523: The death of millions of Germans. The terms of the Peace of Westphalia (1648) ending the war, included a major reduction in the central authority of the Holy Roman Emperor. Among the most powerful German states to emerge in the aftermath was Protestant Prussia , under the rule of the House of Hohenzollern . Charles V and his Habsburg dynasty defended Roman Catholicism. In the 18th century, German culture

5795-509: The end of World War II , defines a German as a German citizen . During the 19th and much of the 20th century, discussions on German identity were dominated by concepts of a common language, culture, descent, and history. Today, the German language is widely seen as the primary, though not exclusive, criterion of German identity. Estimates on the total number of Germans in the world range from 100 to 150 million, most of whom live in Germany. The history of Germans as an ethnic group began with

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5890-439: The entry of microorganisms. Epidermal ceramides have a diversity of structures and can be broadly classified as AS and NS ceramides; ADS and NDS dihydroceramides; AH, EOH, and NH 6-hydroxyceramides; AP and NP phytoceramides; and EOH and EOS acylceramides, see figure. The diversity of ceramide structures undoubtedly plays an important role in the unique attributes of the stratum corneum across different body sites. For example,

5985-461: The events of cell death and some evidence suggests ceramide functions upstream of the mitochondria in inducing apoptosis. However, owing to the conflicting and variable nature of studies into the role of ceramide in apoptosis, the mechanism by which this lipid regulates apoptosis remains elusive. The stratum corneum is the outermost layer of the epidermis . It is composed of terminally differentiated and enucleated corneocytes that reside within

6080-454: The formation of a united German Empire . In the years following unification, German society was radically changed by numerous processes, including industrialization, rationalization, secularization and the rise of capitalism. German power increased considerably and numerous overseas colonies were established. During this time, the German population grew considerably, and many emigrated to other countries (mainly North America), contributing to

6175-727: The growth of the German diaspora . Competition for colonies between the Great Powers contributed to the outbreak of World War I , in which the German, Austro-Hungarian and Ottoman Empires formed the Central Powers , an alliance that was ultimately defeated, with none of the empires comprising it surviving the aftermath of the war. Under the terms of the Treaty of Versailles, the German and Austro-Hungarian Empires were both dissolved and partitioned, resulting in millions of Germans becoming ethnic minorities in other countries. The monarchical rulers of

6270-402: The inner leaflet, further suggesting that there may be sphingomyelin present there. The function of sphingomyelin remained unclear until it was found to have a role in signal transduction . It has been discovered that sphingomyelin plays a significant role in cell signaling pathways. The synthesis of sphingomyelin at the plasma membrane by sphingomyelin synthase 2 produces diacylglycerol, which

6365-431: The king. German kings were elected by members of the noble families, who often sought to have weak kings elected in order to preserve their own independence. This prevented an early unification of the Germans. A warrior nobility dominated the feudal German society of the Middle Ages, while most of the German population consisted of peasants with few political rights. The church played an important role among Germans in

6460-499: The later control of powerful German dynasties it became an important region within modern Germany, and home to its modern capital, Berlin. German population also moved eastwards from the 11th century, in what is known as the Ostsiedlung . Over time, Slavic and German-speaking populations assimilated, meaning that many modern Germans have substantial Slavic ancestry. From the 12th century, many Germans settled as merchants and craftsmen in

6555-868: The leadership of Otto von Bismarck , Prussia expanded its sphere of influence and together with its German allies defeated Denmark in the Second Schleswig War and soon after Austria in the Austro-Prussian War , subsequently establishing the North German Confederation . In 1871, the Prussian coalition decisively defeated the Second French Empire in the Franco-Prussian War , annexing the German speaking region of Alsace-Lorraine . After taking Paris, Prussia and their allies proclaimed

6650-406: The leadership of the Habsburgs the Holy Roman Empire itself remained weak, and by the late Middle Ages much of Lotharingia and Burgundy had come under the control of French dynasts, the House of Valois-Burgundy and House of Valois-Anjou . Step by step, Italy, Switzerland, Lorraine , and Savoy were no longer subject to effective imperial control. Trade increased and there was a specialization of

6745-425: The link between signals from outside the cell to signals to be generated within the cell. Ceramide has also been shown to form organized large channels traversing the mitochondrial outer membrane. This leads to the egress of proteins from the intermembrane space. In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 , a massive altered composition of complex lipids occurs as

6840-673: The liver, and the onset and progression of non-alcoholic fatty liver disease (NAFLD) is associated with elevated ceramide in hepatocytes . Dietary intake of saturated fat has been shown to increase serum ceramide and increase insulin resistance . Although initial studies showed increased insulin resistance in muscle, subsequent studies also showed increased insulin resistance in liver and adipose tissue . Interventions that limit ceramide synthesis or increase ceramide degradation lead to improved health (reduced insulin resistance and reduced fatty liver disease , for example). Ceramides induce skeletal muscle insulin resistance when synthesized as

6935-486: The major lipids in the lipid bilayer . Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely supporting structural elements, ceramide can participate in a variety of cellular signaling : examples include regulating differentiation , proliferation , and programmed cell death (PCD) of cells . The word ceramide comes from the Latin cera ( wax ) and amide . Ceramide

7030-601: The majority of the population. There are also sizable populations of Germans in Austria, Switzerland, the United States, Brazil, France, Kazakhstan, Russia, Argentina, Canada, Poland, Italy, Hungary, Australia, South Africa, Chile, Paraguay, and Namibia. The Germans are marked by great regional diversity, which makes identifying a single German culture quite difficult. The arts and sciences have for centuries been an important part of German identity. The Age of Enlightenment and

7125-440: The means by which ceramide acts as a signaling molecule are not clear. One hypothesis is that ceramide generated in the plasma membrane enhances membrane rigidity and stabilizes smaller lipid platforms known as lipid rafts , allowing them to serve as platforms for signalling molecules. Moreover, as rafts on one leaflet of the membrane can induce localized changes in the other leaflet of the bilayer, they can potentially serve as

7220-460: The most common name for the Germans in English. The term Germans may also be applied to any citizens, natives or inhabitants of Germany, regardless of whether they are considered to have German ethnicity. In some contexts, people of German descent are also called Germans. In historical discussions the term "Germans" is also occasionally used as a way to refer to members of the Germanic peoples during

7315-467: The notion of a Kulturnation (nation sharing a common culture). The German language remains the primary criterion of modern German identity. Ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond . Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up sphingomyelin , one of

7410-493: The painter Caspar David Friedrich , and the composers Johann Sebastian Bach , Ludwig van Beethoven , Wolfgang Amadeus Mozart , Joseph Haydn , Johannes Brahms , Franz Schubert , Richard Strauss and Richard Wagner . Popular German dishes include brown bread and stew . Germans consume a high amount of alcohol , particularly beer, compared to other European peoples. Obesity is relatively widespread among Germans. Carnival (German: Karneval , Fasching , or Fastnacht )

7505-413: The pathway the production of ceramide may influence either the rate and form of cell death or work to release blocks on downstream events. Sphingomyelin, as well as other sphingolipids, are associated with lipid microdomains in the plasma membrane known as lipid rafts . Lipid rafts are characterized by the lipid molecules being in the lipid ordered phase, offering more structure and rigidity compared to

7600-520: The pre-teen years. The brain is not affected. Most patients present with <1% normal levels of the enzyme in comparison to normal levels. A hemolytic protein, lysenin, may be a valuable probe for sphingomyelin detection in cells of Niemann-Pick A patients. As a result of the autoimmune disease multiple sclerosis (MS), the myelin sheath of neuronal cells in the brain and spinal cord is degraded, resulting in loss of signal transduction capability. MS patients exhibit upregulation of certain cytokines in

7695-438: The radiation leads to the activation of sphingomyelinase in the cell membrane and ultimately, to ceramide generation. De novo synthesis of ceramide begins with the condensation of palmitate and serine to form 3-keto-dihydrosphingosine. This reaction is catalyzed by the enzyme serine palmitoyl transferase and is the rate-limiting step of the pathway. In turn, 3-keto-dihydrosphingosine is reduced to dihydrosphingosine , which

7790-650: The rest of the plasma membrane. In the rafts, the acyl chains have low chain motion but the molecules have high lateral mobility. This order is in part due to the higher transition temperature of sphingolipids as well as the interactions of these lipids with cholesterol. Cholesterol is a relatively small, nonpolar molecule that can fill the space between the sphingolipids that is a result of the large acyl chains. Lipid rafts are thought to be involved in many cell processes, such as membrane sorting and trafficking, signal transduction, and cell polarization. Excessive sphingomyelin in lipid rafts may lead to insulin resistance . Due to

7885-592: The same term were also used in the Low Countries , for the related dialects of what is still called Dutch in English, which is now a national language of the Netherlands and Belgium . The first information about the peoples living in what is now Germany was provided by the Roman general and dictator Julius Caesar , who gave an account of his conquest of neighbouring Gaul in the 1st century BC. Gaul included parts of what

7980-590: The separation of a distinct Kingdom of Germany from the eastern part of the Frankish Empire under the Ottonian dynasty in the 10th century, forming the core of the Holy Roman Empire . In subsequent centuries the political power and population of this empire grew considerably. It expanded eastwards, and eventually a substantial number of Germans migrated further eastwards into Eastern Europe . The empire itself

8075-423: The specific types of lipids in these microdomains, lipid rafts can accumulate certain types of proteins associated with them, thereby increasing the special functions they possess. Lipid rafts have been speculated to be involved in the cascade of cell apoptosis. Sphingomyelin can accumulate in a rare hereditary disease called Niemann–Pick disease , types A and B. It is a genetically-inherited disease caused by

8170-487: The sphingosine portion of the molecule, which may then contribute to the generation of ceramides. Ceramide can be further hydrolyzed by acid ceramidase to form sphingosine and a free fatty acid, both of which are able to leave the lysosome, unlike ceramide. The long-chain sphingoid bases released from the lysosome may then re-enter pathways for synthesis of ceramide and/or sphingosine-1-phosphate . The salvage pathway re-utilizes long-chain sphingoid bases to form ceramide through

8265-592: The stratum corneum of the face is thin and flexible to accommodate different facial expressions. In contrast, the stratum corneum covering the heel of the foot is thick and rigid to protect against trauma. Matching these structural changes, there are body-site specific alterations in the epidermal lipidome, including changes in the relative abundance of the different epidermal ceramide structures. Similar to body site-specific alterations in ceramide abundance, there are also well-characterized changes in epidermal ceramide expression in patients with inflammatory skin diseases. In

8360-808: The strongest influence on the likelihood of a particular ceramide structure being upregulated or downregulated in inflamed skin. Ceramide levels in the skin, hair, and nails can be reduced due to environmental changes (such as dry/polluted air), use of harsh sulfates, excessive heat (including heat styling), UV exposure, and biological aging. Inhibition of ceramide synthesis with myriocin in obese mice may lead to both improved leptin signaling and decreased insulin resistance by decreasing SOCS-3 expression. An elevated level of ceramide can cause insulin resistance by inhibiting the ability of insulin to activate the  insulin signal transduction pathway and/or via the activation of  JNK . Currently,

8455-564: The temporary Frankfurt Parliament , but failed in their aim of forming a united German homeland. The Prussians proposed an Erfurt Union of the German states, but this effort was torpedoed by the Austrians through the Punctation of Olmütz (1850), recreating the German Confederation. In response, Prussia sought to use the Zollverein customs union to increase its power among the German states. Under

8550-604: The time of the Roman Empire . The German endonym Deutsche is derived from the Old High German term diutisc , which means "ethnic" or "relating to the people". This term was used for speakers of West-Germanic languages in Central Europe since at least the 8th century, after which time a distinct German ethnic identity began to emerge among at least some them living within the Holy Roman Empire. However, variants of

8645-455: Was crowned emperor by Pope Leo I in 800. In the generations after Charlemagne the empire was partitioned at the Treaty of Verdun (843), eventually resulting in the long-term separation between the states of West Francia , Middle Francia and East Francia . Beginning with Henry the Fowler , non-Frankish dynasties also ruled the eastern kingdom, and under his son Otto I , East Francia, which

8740-570: Was mostly German, constituted the core of the Holy Roman Empire . Also under control of this loosely controlled empire were the previously independent kingdoms of Italy , Burgundy , and Lotharingia . The latter was a Roman and Frankish area which contained some of the oldest and most important old German cities including Aachen , Cologne and Trier , all west of the Rhine. Leaders of the stem duchies which constituted this eastern kingdom — Bavaria , Franconia , Swabia , Thuringia , and Saxony ― continued to wield considerable power independently of

8835-557: Was politically divided between many small princedoms, cities and bishoprics. Following the Reformation in the 16th century, many of these states found themselves in bitter conflict concerning the rise of Protestantism . In the 19th century, the Holy Roman Empire dissolved, and German nationalism began to grow. At the same time however, the concept of German nationality became more complex. The multiethnic Kingdom of Prussia incorporated most Germans into its German Empire in 1871, and

8930-509: Was significantly influenced by the Enlightenment . After centuries of political fragmentation, a sense of German unity began to emerge in the 18th century. The Holy Roman Empire continued to decline until being dissolved altogether by Napoleon in 1806. In central Europe, the Napoleonic wars ushered in great social, political and economic changes, and catalyzed a national awakening among

9025-401: Was then hypothesized that sphingomyelin hydrolysis and ceramide signaling were essential in the decision of whether a cell dies. In the early 2000s new studies emerged that defined a new role for sphingomyelin hydrolysis in apoptosis, determining not only when a cell dies but how. After more experimentation it has been shown that if sphingomyelin hydrolysis happens at a sufficiently early point in

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