Persius/hicric huggingface dataset:
Least squares inference in phylogeny
Least squares inference in phylogeny generates a
phylogenetic tree based on an
-bserved matrix of pairwise genetic distances and
-ptionally a weight
matrix. The goal is to find a tree which satisfies the distance constraints as
best as possible.

# Ordinary and weighted least squares
The discrepancy between the observed pairwise distances D_{ij}
and the distances T_{ij} over a phylogenetic tree (i.e. the sum
-f the branch lengths in the path from leaf i to leaf
j) is measured by
where the weights w_{ij} depend on the least squares method used.
Least squares
distance tree construction aims to find the tree (topology and branch lengths)
with minimal S. This is a non-trivial problem. It involves searching the
discrete space of unrooted binary tree topologies whose size is exponential in
the number of leaves. For n leaves there are
1 - 3 - 5 - ... - (2n-3)
different topologies. Enumerating them is not feasible already for a small
number of leaves. Heuristic search methods are used to find a reasonably
good topology. The evaluation of S for a given topology (which includes the
computation of the branch lengths) is a  linear least squares problem.
There are several ways to weight the squared errors
(D_{ij}-T_{ij})^2,
depending on the knowledge and assumptions about the variances of the observed
distances. When nothing is known about the errors, or if they are assumed to be
independently distributed and equal for all observed distances, then all the
weights w_{ij} are set to one. This leads to an ordinary least
squares estimate.
In the weighted least squares case the errors are assumed to be independent
(or their correlations are not known). Given independent errors, a particular
weight should ideally be set to the inverse of the variance of the corresponding distance
estimate. Sometimes the variances may not be known, but they
can be modeled as a function of the distance estimates. In the Fitch and
Margoliash method
for instance it is assumed that the variances are proportional to the squared
distances.

# Generalized least squares
The ordinary and weighted least squares methods described above
assume independent distance estimates. If the distances
are derived from genomic data their estimates covary, because evolutionary
events on internal
branches (of the true tree) can push several distances up or down at
the same time. The resulting covariances can be taken into account using the
method of generalized least squares, i.e. minimizing the following quantity
where w_{ij,kl} are the entries of the inverse of the covariance matrix of the distance estimates.
Lecithincholesterol acyltransferase
Lecithincholesterol acyltransferase (LCAT, also called phosphatidylcholinesterol O-acyltransferase) is an enzyme that converts free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become unidirectional since the particles are removed from the surface. The enzyme is bound to high-density lipoproteins (HDLs) (alpha-LCAT) and LDLs (beta-LCAT) in the blood plasma. LCAT deficiency can cause impaired vision due to cholesterol corneal opacities, anemia, and kidney damage. It belongs to the family of phospholipid:diacylglycerol acyltransferases.

# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. 
-  The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Legg-Calve-Perthes syndrome overview

# Overview
Legg-Calve-Perthes syndrome is a degenerative disease of the hip joint, where a loss of bone mass leads to some degree of collapse of the hip joint, that is, to deformity of the ball of the femur and the surface of the hip socket.  The disease is typically found in young children and small dogs, and it can lead to osteoarthritis in adults.
It is the idiopathic avascular osteonecrosis of the capital femoral epiphysis of the femoral head. It is caused by an interruption to the blood supply of the head of the femur close to the hip joint. It is equivalent to adult avascular necrosis.
It is also known as  Perthes disease, ischemic necrosis of the hip, coxa plana, osteochondritis and avascular necrosis of the femoral head, or Legg-Perthes Disease or Legg-Calve-Perthes Disease (LCPD).
Lightheadedness and vertigo overview

# Overview
Lightheadedness is a common and often unpleasant sensation of dizziness and/or feeling that one may be about to  faint, which may be transient, recurrent, or occasionally chronic.  In some cases, the individual may feel as though his or her head is weightless. It can be simply an indication of a temporary shortage of blood or oxygen to the brain, low blood pressure, low blood sugar, or anemia. It can also be a symptom of many other conditions, some of them serious, such as heart disease, stroke, or bleeding.
Vertigo, a specific type of dizziness, is a major symptom of a balance disorder. It is the sensation of spinning or swaying while the body is stationary with respect to the earth or surroundings. There are two types of vertigo: subjective and objective. Subjective vertigo is when a person feels a false sensation of movement. Objective vertigo is when the surroundings will appear to move past a person's field of vision.
The effects of vertigo may be slight. It can cause nausea and vomiting and, if severe, may give rise to difficulty with standing and walking.
The word "vertigo" comes from the Latin "vertere", to turn + the suffix "-igo", a condition = a condition of turning about.

# Classification
Vertigo is typically classified into one of two categories depending on the location of the damaged vestibular pathway. These are peripheral or central vertigo. Each category has a distinct set of characteristics and associated findings. Vertigo can also occur after long flights or boat journeys where the mind gets used to turbulence, resulting in a person feeling as if they are moving up and down. This usually subsides after a few days.

# Causes
Vertigo is usually associated with a problem in the inner ear balance mechanisms (vestibular system), in the brain, or with the nerve connections between these two organs. Vertigo-like symptoms may also appear as paraneoplastic syndrome (PNS) in the form of opsoclonus myoclonus syndrome, a multi-faceted neurological disorder associated with many forms of incipient cancer lesions or virus. If conventional therapies fail, consult with a neuro-oncologist familiar with PNS.

# Differentiating Lightheadedness and Vertigo from Other Symptoms
A number of specific conditions can cause vertigo.  In the elderly, however, the condition is often multifactorial.

# Treatment

## Medical Therapy
Treatment for lightheadedness can include drinking plenty of water or other fluids (unless the lightheadedness is the result of water intoxicationin which case drinking water is quite dangerous), eating something sugary, and lying down or sitting and reducing the elevation of the head relative to the body (for example by positioning the head between the knees). On the other hand, specific treatment is required for central causes of vertigo.
Lincomycin dosage and administration

# DOSAGE AND ADMINISTRATION
If significant diarrhea occurs during therapy, this antibiotic should be discontinued. (See WARNING box.)

## INTRAMUSCULAR
Adults
Serious infections600 mg (2 mL) intramuscularly every 24 hours. More severe infections600 mg (2 mL) intramuscularly every 12 hours or more often.
Pediatric patients over 1 month of age
Serious infectionsone intramuscular injection of 10 mg/kg (5 mg/lb) every 24 hours. More severe infectionsone intramuscular injection of 10 mg/kg (5 mg/lb) every 12 hours or more often.

## INTRAVENOUS
Adults
The intravenous dose will be determined by the severity of the infection. For serious infections doses of 600 mg of lincomycin (2 mL of LINCOCIN) to 1 gram are given every 8 to 12 hours. For more severe infections these doses may have to be increased. In life-threatening situations daily intravenous doses of as much as 8 grams have been given. Intravenous doses are given on the basis of 1 gram of lincomycin diluted in not less than 100 mL of appropriate solution (see PHYSICAL COMPATIBILITIES) and infused over a period of not less than one hour.
These doses may be repeated as often as required to the limit of the maximum recommended daily dose of 8 grams of lincomycin.
Pediatric patients over 1 month of age
10 to 20 mg/kg/day (5 to 10 mg/lb/day) depending on the severity of the infection may be infused in divided doses as described above for adults.
NOTE: Severe cardiopulmonary reactions have occurred when this drug has been given at greater than the recommended concentration and rate.

## SUBCONJUNCTIVAL INJECTION
0.25 mL (75 mg) injected subconjunctivally will result in ocular fluid levels of antibiotic (lasting for at least 5 hours) with MICs sufficient for most susceptible pathogens.
Patients with diminished renal function
When therapy with LINCOCIN is required in individuals with severe impairment of renal function, an appropriate dose is 25 to 30% of that recommended for patients with normally functioning kidneys.
List of drugs affected by grapefruit

# Overview
Grapefruit and grapefruit juice has the potential to interaction with numerous drugs.  This is due to the fruit's relatively high concentration of naringin, bergamottin, and dihydroxybergamottin, which interfere with the intestinal enzyme cytochrome P450 isoform CYP3A4. However, bioactive compounds in grapefuit juice may also interfere with p-glycoprotein and organic anion transporting polypeptides (OATPs) either increasing or decreasing bioavailability of a number of drugs.

# Affected drugs
The following drugs interact with CYP3A4:
- Bupropion, amfebutamone, Wellbutrin -  rxlist.com
- Valproate semisodium, divalproex sodium, Depakote, Epival - stanford.edu
- Benzodiazepines, including: alprazolam (Xanax), diazepam (Valium), midazolam (Versed), lorazepam (Ativan), oxazepam, and chlordiazepoxide (Librium) - 
- The antihistamine astemizole, fexofenadine
Additional drugs found to be affected by grapefruit juice include, but are not limited to:
- Statins such as atorvastatin, lovastatin, and simvastatin 
- Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), difedipine, nisoldipine (Sular), nitrendipine (Bayotensin) 
- losartan (Cozaar) 
- repaglinide (Prandin) 
- verapamil (Calan SR, Covera HS, Isoptin SR, Verelan) 
- Antiarrhythmics including amiodarone (Cordarone), quinidine (Quinidex, Cardioquin, Quinora), disopyramine (Norpace), propafenone (Rhythmol), and carvediol 
- The male impotence drugs sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)  
- The anti-migraine drugs ergotamine (Cafergot, Ergomar) and nimodipine (Nimotop) 

# Effects on enzymes
Grapefruit juice interacts with many oral drugs.  Compounds in the juice including bergamottin, dihydroxybergamottin, and some flavonoids such as naringin effect the activity of certain intestinal enzymes including CYP3A4 and CYP1A2.
These cytochrome P450 enzymes, which metabolize many drugs, are inhibited by grapefruit juice.  As a result, serum drug concentrations increase, and may become toxic.  This is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic success and toxicity. Grapefruit juice only inhibits the enzyme within the intestines, not in the liver or elsewhere in the body, and does not impact injected drugs. The degree of the effect varies widely between individuals and between samples of juice, therefore it cannot be accounted for a priori.
Recently some researchers have shown that furanocoumarins, rather than flavonoids, may be the ingredients causing the various drug interactions.
The flavonoid existing in highest concentration in grapefruit juice is naringin, which in humans is metabolized to naringenin.  Other flavonoids exist in grapefruit juice in lower concentrations as well.  Orange juice does not contain naringin in as high a concentration, instead containing hesperetin.  It is sometimes recommended as a substitute. Juice of limes and Seville oranges can also inhibit drug metabolism, however, as can apple juice with some drugs.
Long QT syndrome laboratory findings

# Overview
An elevated/reduced concentration of serum/blood/urinary/CSF/other  is diagnostic of .
OR
Laboratory findings consistent with the diagnosis of  include , , and .
OR
 is usually normal for patients with .
OR
Some patients with  may have elevated/reduced concentration of , which is usually suggestive of .
OR
There are no diagnostic laboratory findings associated with .

# Laboratory Findings
There are no diagnostic laboratory findings associated with .
OR
An elevated/reduced concentration of serum/blood/urinary/CSF/other  is diagnostic of .
OR
 is usually normal among patients with .
OR
Laboratory findings consistent with the diagnosis of  include:
OR
Some patients with  may have elevated/reduced concentration of , which is usually suggestive of .
Luteinizing hormone beta polypeptide
Luteinizing hormone subunit beta also known as lutropin subunit beta or LH is a polypeptide that in association with an alpha subunit common to all gonadotropin hormones forms the reproductive signaling molecule luteinizing hormone.  In humans it is encoded by the LHB gene.

# Gene
The luteinizing hormone beta subunit is encoded by a single gene in all mammals.  In primates, this gene is located within a cluster that arose through gene duplication, and also includes multiple redundant genes encoding the beta subunit of chorionic gonadotropin as well as several nonfunctional pseudogenes.  In humans these are contiguous on chromosome 19q13.3. In equids the beta subunit polypeptides of luteinizing hormone and chorionic gonadotropin are identical in sequence, differing only in their carbohydrate side-chains, and are the product of a single gene.

# Function
This gene is a member of the glycoprotein hormone beta chain family and encodes the beta subunit of luteinizing hormone (LH). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and a unique beta subunit (this protein) which confers biological specificity. LH is expressed in the pituitary gland and promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.

# Clinical significance
Mutations in this gene are associated with hypogonadism which is characterized by infertility and pseudohermaphroditism.
Lymphangiomyomatosis medical therapy
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# Overview

# Medical Therapy
The association of LAM with women of childbearing age suggests that hormonal stimulation plays a role in the disease process, and several approaches to treatment involve diminishing the effect of estrogen.  At one time or another, therapeutic approaches have included
- progesterone
- oophorectomy
- tamoxifen
- gonadotropin-releasing hormone (GnRH) agonists
- androgen therapy
No therapy is clearly efficacious, and all have undesirable side-effects.  There is some evidence which shows that tamoxifen may actually cause worsening of LAM in some patients.
Muscarinic acetylcholine receptor M1
The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor that in humans is encoded by the CHRM1 gene. It is localized to 11q13.
This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS.
It is predominantly found bound to G proteins of class Gq that use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, Gi (causing a downstream decrease in cAMP) and Gs (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX respectively.

# Effects
- EPSP in autonomic ganglia
- Secretion from salivary glands
- Gastric acid secretion from stomach
- In CNS (memory?)
- Vagally-induced bronchoconstriction
- Mediating olfactory behaviors (e.g. aggression, mating)

# Orthologs
In search of evolutionary origins of cholinergic system and muscarinic receptors in eukaryotes, a structural homolog of M1 receptor has been reported in Acanthamoeba castellanii. and Naegleria fowleri. The receptor antagonists of M1 receptors have shown to be exert anti-proliferative effects on these amoebae.

# Mechanism
It couples to Gq, and, to a small extent, Gi and Gs. This results in slow EPSP and decreased K+ conductance. It is preassembled to the Gq heterotrimer through a polybasic c-terminal domain.

# Ligands

## Agonists
- acetylcholine
- carbachol
- cevimeline
- muscarine
- oxotremorine
- pilocarpine
- vedaclidine
- xanomeline
- 77-LH-28-1 - brain penetrant selective M1 allosteric agonist
- CDD-0097
- McN-A-343 - mixed M1/M4 agonist
- L-689, L-660 - mixed M1/M3 agonist

## Allosteric modulators
- benzylquinolone carboxylic acid
- BQZ-12
- VU-0090157
- VU-0029767
- PT-1284- M1-selective PAM Radioligand

## Antagonists
- atropine
- diphenhydramine
- dicycloverine
- hyoscyamine
- ipratropium
- mamba toxin muscarinic toxin 7 (MT7)
- Many antipsychotics like olanzapine, quetiapine, clozapine,  chlorpromazine
- pirenzepine
- oxybutynin
- Benzatropine
- telenzepine
- Tricyclic and tetracyclic antidepressants like clomipramine, imipramine, mirtazapine, amitriptyline
- tolterodine
- Biperiden
Muscarinic acetylcholine receptor M2
The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the CHRM2 gene. Multiple alternatively spliced transcript variants have been described for this gene.

# Function

## Heart
The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after positive stimulatory actions of the parasympathetic nervous system, by slowing the speed of depolarization. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). However, they have little effect on the contractile forces of the ventricular muscle, slightly decreasing force.

## IQ
A Dutch family study found that there is "a highly significant association" between the CHRM2 gene and intelligence as measured by the Wechsler Adult Intelligence Scale-Revised. A similar association was found independently in the Minnesota Twin and Family Study.
However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence.

## Olfactory behavior
Mediating olfactory guided behaviors (e.g. odor discrimination, aggression, mating).

# Mechanism of action
M2 muscarinic receptors act via a Gi type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to serve as autoreceptors.
In addition, they modulate muscarinic potassium channels. In the heart, this contributes to a decreased heart rate. They do so by the G subunit of the G protein; G opens K+ channels in the parasympathetic notches in the heart, which causes an outward current of potassium, which slows down the heart rate.

# Ligands
Few highly selective M2 agonists are available at present, although there are several non-selective muscarinic agonists that stimulate M2, and a number of selective M2 antagonists are available.

## Agonists
- (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide (selective for M2 but only partial agonist)
- Berberine
- Iper-8-naph (compound 8b, bitopic/dualsteric agonist)
- Methacholine

## Antagonists
- AFDX-384
- Atropine
- Chlorpromazine
- Dicycloverine
- Dimenhydrinate
- Dimethindene
- Diphenhydramine
- Gallamine
- Hyoscyamine
- Ipratropium
- Methoctramine
- Otenzepad
- Oxybutynin
- Thorazine
- Tolterodine
- Tripitramine
mRNA (guanine-N7-)-methyltransferase
In enzymology, a mRNA (guanine-N7-)-methyltransferase also known as mRNA cap guanine-N7 methyltransferase is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are S-adenosyl methionine and G(5')pppR-RNA, whereas its two products are S-adenosylhomocysteine and m7G(5')pppR-RNA. This enzyme belongs to the family of transferases, specifically those transferring one-carbon group methyltransferases.
In humans, mRNA cap guanine-N7 methyltransferase is encoded by the RNMT gene.

# Nomenclature
The systematic name of this enzyme class is S-adenosyl-L-methionine:mRNA (guanine-N7-)-methyltransferase. Other names in common use include:
- messenger ribonucleate guanine 7-methyltransferase,
- guanine-7-methyltransferase,
- messenger RNA guanine 7-methyltransferase, and
- S-adenosyl-L-methionine:mRNA (guanine-7-N-)-methyltransferase.
- cap MTase