on 29-Aug-2020 (Sat)

There are true hardcore DSPS cases with some psychiatric overtones or other health issues that might be particularly intractable, however, those should form a rare minority in the ever-increasing mass of people struggling with DSPS. That mass now includes a countless population of insomniacs who have never heard of DSPS and never even arrived to the problem of phase shift due to the employment of the alarm clock. Weitzman hypothesized that a significant number of patients with sleep onset insomnia might be suffering from undiagnosed DSPS (Weitzman et al. 1981^[35]). Now we know that hypothesis certainly holds true, which can be demonstrated by letting insomniacs free run their sleep. A significant phase delay may be observed within the first few days of such a release from the restrictions on the timing of sleep. At the same time, there is an accompanying and nearly instant disappearance of sleep-onset insomnia.

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rare minority of people have pathological DSPS.

much of insomnia might be DSPS in disguise: Phase shift simply doesn't occur due to alarm clocks. When these "insomniacs" free run sleep, insomnia disappears, but phase shifts occur.

in real analysis, a branch of mathematics, a slowly varying function is a function of a real variable whose behaviour at infinity is in some sense similar to the behaviour of a function converging at infinity. Similarly, a regularly varying function is a function of a real variable whose behaviour at infinity is similar to the behaviour of a power law function (like a polynomial) near infinity.

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this makes sense now: ln(x) "converges" at infinity, i.e. if x = infinity, the function doesn't grow anymore! This is bc to increase value of ln(x) by constant, you'd e.g. need to double x - in this sense it has converged.

regularly varying functions behave like power law functions because if you scale input argument, the function grows by a function of the scale (as opposed to e.g. exponentials, where scaling input scales output by the output - hence exponential: growth depends on itself)

This concept is often contrasted with uniform convergence. To say that

\(\lim_{n\rightarrow\infty}f_n=f\ \mbox{uniformly}\)

means that

\({\displaystyle \lim _{n\rightarrow \infty }\,\sup\{\,\left|f_{n}(x)-f(x)\right|:x\in A\,\}=0,}\)

where \(A\) is the common domain of \(f\) and \(f_{n}\). That is a stronger statement than the assertion of pointwise convergence: every uniformly convergent sequence is pointwise convergent, to the same limiting function, but some pointwise convergent sequences are not uniformly convergent. For example, if \({\displaystyle f_{n}:[0,1)\rightarrow [0,1)}\) is a sequence of functions defined by \(f_{n}(x)=x^{n}\), then \({\displaystyle \lim _{n\rightarrow \infty }f_{n}(x)=0}\) pointwise on the interval [0,1), but not uniformly.

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i've missed some intuition first time around: in closed domain, pointwise = uniform convergence (because sup = max, and this max x needs to converge by pointwise criteria as well). For pointwise, every "point" x, the function family f_n approaches f. Can imagine this as one function slowly creeping towards the other one. The speed of convergence doesn't matter. For uniform it's somewhat different: For open intervals, there might be a supremum that doesn't converge, while all xs converge (i.e. we have pointwise, but not uniform convergence). This means for some given n, the functions have nearly approached each other, but towards boundary of domain, we can always find an x that still hasn't approached f. It refuses to approach, so to speak. It's probably called "uniform convergence" because if it holds, then all x's (even the ones at boundary) converge uniformly - as opposed to example before, where we could find f_n(x)'s at domain boundary that stayed far away from f.

In macroeconomics, the money supply (or money stock) is the total value of money available in an economy at a point of time. There are several ways to define "money", but standard measures usually include currency in circulation and demand deposits (depositors' easily accessed assets on the books of financial institutions).^[1][2] The central bank of each country may use a definition of what constitutes money for its purposes

A transaction account, also called a checking account, chequing account, current account, demand deposit account, or share draft account at credit unions, is a deposit account held at a bank or other financial institution. It is available to the account owner "on demand" and is available for frequent and immediate access by the account owner or to others as the account owner may direct. Access may be in a variety of ways, such as cash withdrawals, use of debit cards, cheques (checks) and electronic transfer. In economic terms, the funds held in a transaction account are regarded as liquid funds. In accounting terms they are considered as cash.

Demand deposits, or non confidential money are funds held in demand accounts in commercial banks.^[1] These account balances are usually considered money and form the greater part of the narrowly defined money supply of a country

This new money makes up the non-M0 components in the M1-M3 statistics. In short, there are two types of money in a fractional-reserve banking system:^[7][8][9]

• central bank money — obligations of a central bank, including currency and central bank depository accounts
• commercial bank money — obligations of commercial banks, including checking accounts and savings accounts.

In the money supply statistics, central bank money is MB while the commercial bank money is divided up into the M1-M3 components. Generally, the types of commercial bank money that tend to be valued at lower amounts are classified in the narrow category of M1 while the types of commercial bank money that tend to exist in larger amounts are categorized in M2 and M3, with M3 having the largest

Commercial banks play a role in the process of money creation, especially under the fractional-reserve banking system used throughout the world. In this system, money is created whenever a bank gives out a new loan. This is because the loan, when drawn on and spent, mostly finishes up as a deposit in the banking system, which is counted as part of money supply. After putting aside a part of these deposits as mandated bank reserves, the balance is available for the making of further loans by the bank. This process continues multiple times, and is called the multiplier effect.

Fractional-reserve banking, the most common form of banking practised by commercial banks worldwide,^[1][2] involves banks accepting deposits from customers and making loans to borrowers while holding in reserve an amount equal to only a fraction of the bank's deposit liabilities.^[3] Bank reserves are held as cash in the bank or as balances in the bank's account at a central bank. The country's central bank determines the minimum amount that banks must hold in liquid assets, called the "reserve requirement" or "reserve ratio". Banks usually hold more than this minimum amount, keeping excess reserves.

A userscript (or user script) is a program, usually written in JavaScript, for modifying web pages^[1] to augment browsing. On desktop browsers such as Firefox, they are enabled by use of a userscript manager browser extension such as Greasemonkey

When a company deposits cash with a bank, the bank records a liability on its balance sheet, representing the obligation to repay the depositor, usually on demand.

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of course also holds for people depositing cash.

In financial accounting, a liability is defined as the future sacrifices of economic benefits that the entity is obliged to make to other entities as a result of past transactions or other past events

In finance, equity is ownership of assets that may have debts or other liabilities attached to them. Equity is measured for accounting purposes by subtracting liabilities from the value of an asset. For example, if someone owns a car worth $9,000 and owes $3,000 on the loan used to buy the car, then the difference of $6,000 is equity. Equity can apply to a single asset, such as a car or house, or to an entire business

In financial accounting, an asset is any resource owned by a business or an economic entity. It is anything (tangible or intangible) that can be owned or controlled to produce value and that is held by an economic entity and that could produce positive economic value. Simply stated, assets represent value of ownership that can be converted into cash (although cash itself is also considered an asset).

Eigenkapital ist in den Wirtschaftswissenschaften derjenige Teil des Kapitals von Wirtschaftssubjekten, der sich bilanziell als positive Differenz aus Vermögen und Schulden zeigt, so dass das Eigenkapital dem Reinvermögen entspricht. Eine gleichberechtigte Definition geht davon aus, dass das Eigenkapital den Wirtschaftssubjekten zeitlich unbefristet zur Verfügung steht und somit keiner Rückzahlungsverpflichtung unterliegt.

Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues

Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus.^[3][4] Histamine is involved in the inflammatory response and has a central role as a mediator of itching

A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed by the reception of a proton (H⁺) by a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a hydrogen ion. On the other hand, a conjugate base is what is left over after an acid has donated a proton during a chemical reaction. Hence, a conjugate base is a species formed by the removal of a proton from an acid, as in the reverse reaction it is able to gain a hydrogen ion.^[1] Because some acids are capable of releasing multiple protons, the conjugate base of an acid may itself be acidic.

In summary, this can be represented as the following chemical reaction:

Acid + Base ⇌ Conjugate Base + Conjugate Acid

In chemistry, protonation (or hydronation) is the addition of a proton (or hydron, or hydrogen cation), (H⁺) to an atom, molecule, or ion, forming the conjugate acid.^[1] Some examples include

• the protonation of water by sulfuric acid: H₂SO₄ + H₂O ⇌ H₃O⁺ + HSO ⁻
  ₄

Although histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in 23 different physiological functions. Histamine is known to be involved in many physiological functions because of its chemical properties that allow it to be versatile in binding.

It has been known for more than one hundred years that an intravenous injection of histamine causes a fall in the blood pressure

Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction: a runny nose and watery eyes

It supports a variety of functions including emotion, behavior, motivation, long-term memory, and olfaction.^[2] Emotional life is largely housed in the limbic system, and it critically aids the formation of memories

Histaminergic means "working on the histamine system", and histaminic means "related to histamine".

A histaminergic agent (or drug) is a chemical which functions to directly modulate the histamine system in the body or brain

The tuberomammillary nucleus is a histaminergic nucleus located within the posterior third of the hypothalamus.^[1] It consists of, largely, histaminergic neurons (i.e., histamine-releasing neurons) and is involved with the control of arousal, learning, memory, sleep and energy balance.^[1]

The expression of NF-κB, the transcription factor that regulates inflammatory processes, is promoted by the constitutive activity of the H₁ receptor as well as by agonists that bind at the receptor.^[7] H₁-antihistamines have been shown to attenuate NF-κB expression and mitigate certain inflammatory processes in associated cells

The H₁ receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system.

Endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels, and lymphatic vessels.^[1] The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Endothelial cells in direct contact with blood are called vascular endothelial cells whereas those in direct contact with lymph are known as lymphatic endothelial cells. Vascular endothelial cells line the entire circulatory system, from the heart to the smallest capillaries.

These cells have unique functions that include fluid filtration, such as in the glomerulus of the kidney, blood vessel tone, hemostasis, neutrophil recruitment, and hormone trafficking. Endothelium of the interior surfaces of the heart chambers is called endocardium. An impaired function can lead to serious health issues throughout the body.

Squamous cells have the appearance of thin, flat plates that can look polygonal when viewed from above.^[12] Their name comes from squāma, Latin for "scale" – as on fish or snake skin. The cells fit closely together in tissues, providing a smooth, low-friction surface over which fluids can move easily. The shape of the nucleus usually corresponds to the cell form and helps to identify the type of epithelium. Squamous cells tend to have horizontally flattened, nearly oval-shaped nuclei because of the thin, flattened form of the cell. Squamous epithelium is found lining surfaces such as skin or alveoli in the lung, enabling simple passive diffusion as also found in the alveolar epithelium in the lungs

The endothelium is a thin layer of single flat (squamous) cells that line the interior surface of blood vessels and lymphatic vessels.^[2]

The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. This forms a barrier between vessels and tissues and control the flow of substances and fluid into and out of a tissue. This controls the passage of materials and the transit of white blood cells into and out of the bloodstream. Excessive or prolonged increases in permeability of the endothelium, as in cases of chronic inflammation, may lead to tissue swelling (edema).

Antihistamines, which act on this receptor, are used as anti-allergy drugs

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein.

High concentrations of myoglobin in muscle cells allow organisms to hold their breath for a longer period of time. Diving mammals such as whales and seals have muscles with particularly high abundance of myoglobin

Myoglobin is distantly related to hemoglobin,^[8][10] oxygen-binding protein in red blood cells. In humans, myoglobin is only found in the bloodstream after muscle injury

Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the skeletal muscle tissue of vertebrates in general and in almost all mammals

Myoglobin was the first protein to have its three-dimensional structure revealed by X-ray crystallography.^[14] This achievement was reported in 1958 by John Kendrew and associates

Myoglobin contains hemes, pigments responsible for the colour of red meat. The colour that meat takes is partly determined by the degree of oxidation of the myoglobin. In fresh meat the iron atom is in the ferrous (+2) oxidation state bound to an oxygen molecule (O₂). Meat cooked well done is brown because the iron atom is now in the ferric (+3) oxidation state, having lost an electron. If meat has been exposed to nitrites, it will remain pink because the iron atom is bound to NO, nitric oxide (true of, e.g., corned beef or cured hams). Grilled meats can also take on a pink "smoke ring" that comes from the iron binding to a molecule of carbon monoxide.^[20] Raw meat packed in a carbon monoxide atmosphere also shows this same pink "smoke ring" due to the same principles

Binding occurs by intermolecular forces, such as ionic bonds, hydrogen bonds and Van der Waals forces. The association or docking is actually reversible through dissociation. Measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry, in biochemistry it is ambiguous whether the ligand generally binds at a metal site, as is the case in hemoglobin. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed. The etymology stems from ligare, which means 'to bind'.

A biogenic substance is a product made by or of life forms. The term encompasses constituents, secretions, and metabolites of plants or animals

A connection table is in essence a graph containing the complete and explicit description of molecular topology and forms an easily analyzable repository of 2D chemical data for VS. Graph theory forms the mathematical model at the core of topology description, 12–15 and many of the key concepts of molecular graph theory are highlighted in Figure 1 .

Virtual screening techniques have become an increasingly important tool for lead discovery. Whether used in conjunction with HTS or stand alone, VS techniques provide a quick and economical method for the discovery of novel actives

VS is a computational technique which uses computer programs to search potential hits from virtual fragment libraries. ^{47 , 48} There are two widely used approaches for VS: Structure-based methods (docking) and ligand-based methods. ⁴⁹ In contrast to experimental methods, VS, on the one hand, is fast and cost-effective, but on the other hand, has relatively low accuracy of predictions and rapid accumulation of errors.

The crystal structure of the receptor has been determined and used to discover new histamine H₁ receptor ligands in structure-based virtual screening studies [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228891/]

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virtual screen studies are drug tests (screening), except virtual. Finding new H1 receptor ligands (i.e. things that bind to H1 receptor) is useful because it allows to invent drugs that can dock and thus block H1 receptor (I'm supposing)

The optimized in silico screening approach was successfully applied to identify a chemically diverse set of novel fragment-like (≤ 22 heavy atoms) H₁R ligands with an exceptionally high hit rate of 73%.

Histamine receptors exhibit constitutive activity, so antihistamines can function as either a neutral receptor antagonist or an inverse agonist at histamine receptors

A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity".

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in natural works of receptor protein.^[1] They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors.

Dose response curves of a full agonist, partial agonist, neutral antagonist, and inverse agonist

A prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as intrinsic or basal) level of activity in the absence of any ligand.^[3] An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level.

A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either

An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist

Typically people take antihistamines as an inexpensive, generic, over-the-counter drug that can provide relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects

Mechanism of NF-κB action. In this figure, the NF-κB heterodimer consisting of Rel and p50 proteins is used as an example. While in an inactivated state, NF-κB is located in the cytosol complexed with the inhibitory protein IκBα. Through the intermediacy of integral membrane receptors, a variety of extracellular signals can activate the enzyme IκB kinase (IKK). IKK, in turn, phosphorylates the IκBα protein, which results in ubiquitination, dissociation of IκBα from NF-κB, and eventual degradation of IκBα by the proteasome. The activated NF-κB is then translocated into the nucleus where it binds to specific sequences of DNA called response elements (RE). The DNA/NF-κB complex then recruits other proteins such as coactivators and RNA polymerase, which transcribe downstream DNA into mRNA. In turn, mRNA is translated into protein, resulting in a change of cell function

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.^{[1][2][3][5][6]} NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development