A theoretical investigation of the effect of proliferation & adhesion on monoclonal conversion in the colonic crypt

The surface epithelium lining the intestinal tract renews itself rapidly by a coordinated programme of cell proliferation, migration and differentiation events that is initiated in the crypts of Lieberkühn. It is generally believed that colorectal cancer arises due to mutations that disrupt the normal cellular dynamics of the crypts. Using a spatially structured cell-based model of a colonic crypt, we investigate the likelihood that the progeny of a mutated cell will dominate, or be sloughed out of, a crypt. Our approach is to perform multiple simulations, varying the spatial location of the initial mutation, and the proliferative and adhesive properties of the mutant cells, to obtain statistical distributions for the probability of their domination. Our simulations lead us to make a number of predictions. The process of monoclonal conversion always occurs, and does not require that the cell which initially gave rise to the population remains in the crypt. Mutations occurring more than one to two cells from the base of the crypt are unlikely to become the dominant clone. The probability of a mutant clone persisting in the crypt is sensitive to dysregulation of adhesion. By comparing simulation results with those from a simple one-dimensional stochastic model of population dynamics at the base of the crypt, we infer that this sensitivity is due to direct competition between wild-type and mutant cells at the base of the crypt. We also predict that increases in the extent of the spatial domain in which the mutant cells proliferate can give rise to counter-intuitive, non-linear changes to the probability of their fixation, due to effects that cannot be captured in simpler models

A theoretical investigation of the effect of proliferation and\ud adhesion on monoclonal conversion in the colonic crypt

Colorectal cancers are initiated by the accumulation of mutations in the colonic epithelium. Using a spatially structured cell-based model of a colonic crypt, we investigate the likelihood that the progeny of a mutated cell will dominate, or be sloughed out of, a crypt. Our approach is to perform multiple simulations, varying the spatial location of the initial mutation, and its proliferative and adhesive properties, to obtain statistical distributions for the probability of domination. Our simulations lead us to make a number of predictions. The process of monoclonal conversion always occurs, and does not require that the cell which initially gave rise to the population remains in the crypt. Mutations occurring more than one to two cells from the base of the crypt are unlikely to become the dominant clone. The probability of a mutant clone persisting in the crypt is sensitive to dysregulation of adhesion, and comparison with a one-dimensional model suggests that this is caused by competition directly at the base of the crypt.\ud We also predict that increases in the extent of the spatial domain in which the mutant cells proliferate cause counter-intuitive non-linear changes to the probability of its fixation, due to effects that cannot be captured in simpler models

Disruptive Innovations and Disruptive Assurance: Assuring Machine Learning and Autonomy

Autonomous and machine learning-based systems are disruptive innovations and thus require a corresponding disruptive assurance strategy. We offer an overview of a framework based on claims, arguments, and evidence aimed at addressing these systems and use it to identify specific gaps, challenges, and potential solutions

A dispersive wave pattern on Jupiter's fastest retrograde jet at 20∘20^\circS

A compact wave pattern has been identified on Jupiter's fastest retrograding jet at 20S (the SEBs) on the southern edge of the South Equatorial Belt. The wave has been identified in both reflected sunlight from amateur observations between 2010 and 2015, thermal infrared imaging from the Very Large Telescope and near infrared imaging from the Infrared Telescope Facility. The wave pattern is present when the SEB is relatively quiescent and lacking large-scale disturbances, and is particularly notable when the belt has undergone a fade (whitening). It is generally not present when the SEB exhibits its usual large-scale convective activity ('rifts'). Tracking of the wave pattern and associated white ovals on its southern edge over several epochs have permitted a measure of the dispersion relationship, showing a strong correlation between the phase speed (-43.2 to -21.2 m/s) and the longitudinal wavelength, which varied from 4.4-10.0 deg. longitude over the course of the observations. Infrared imaging sensing low pressures in the upper troposphere suggest that the wave is confined to near the cloud tops. The wave is moving westward at a phase speed slower (i.e., less negative) than the peak retrograde wind speed (-62 m/s), and is therefore moving east with respect to the SEBs jet peak. Unlike the retrograde NEBn jet near 17N, which is a location of strong vertical wind shear that sometimes hosts Rossby wave activity, the SEBs jet remains retrograde throughout the upper troposphere, suggesting the SEBs pattern cannot be interpreted as a classical Rossby wave. Cassini-derived windspeeds and temperatures reveal that the vorticity gradient is dominated by the baroclinic term and becomes negative (changes sign) in a region near the cloud-top level (400-700 mbar) associated with the SEBs, suggesting a baroclinic origin for this meandering wave pattern. [Abr]Comment: 19 pages, 11 figures, article accepted for publication in Icaru

3,4,6-Tri-O-acetyl-2-(N-acetylacetamido )-1,2-dideoxy-o-Iyxohex- 1-enopyranose, an Acetamido-n-galactal Derivative, and the Mechanism of its Formation from 2-Acetamido-2-deoxy-D-galactose

The structure of an unsaturated amino sugar derivative, formed in low yield when 2-acetamido-2-deoxy-o-galactose _is treated with boiling isopropenyl acetate containing a trace of p-toluenesulfonic acid, and formulated as 1,4,6-tri-0-acetyl-2-(N-acetylacetamido)- 2,3-dideoxy-o-threo-hex-2-enopyranose(II) in an earlier publication, has been re-examined. Through a series of steps, including catalytic hydrogenation, the substance has been converted into a compound with an NMR spectrum which shows it to be 3,4,6-tri- 0-acetyl-2-(N -acetylbenzamido )-1,5-anhydro-2-deoxy-o-tali tol (X). This fact, together with a re-examination of its NMR spectrum, show the unsaturated compound to be 3,4,6-tri-0-acetyl-2-(N·· -acetylacetamido)-1,2-dideoxy-o-lyxo-hex-l-enopyranose (III), a derivative of 2-acetamido-o-galactal (VI). The yield of III from 2-acetamido-2-deoxy-o-galactose has been substantially improved through isolation of . 2-acetamido-1,3,4 , 6-tetra-0-acetyl-2-deoxy-~- o-galactopyranose (XIII) as an intermediate and III has been obtained in crystalline form. Evidence for the mechanism of its formation is presented

The Behavior of 2-Acetamido-2-deoxy-o-galactose with Isopropenyl Acetate in the Presence of p-Toluenesulfonic Acid. Formation of an Unsaturated Aminosugar Derivative

Treatment of 2-acetamido-2-deoxy-n-galactose (III) with isopropenyl acetate and p-toluenesulfonic acid gives 2-(n-glycero-1,2- -diacetoxyethyl)-4-(N-acetylacetamido) furan (II), the anomeric 1,3, 4,6-te tra-O-acety 1- 2-(N -acetylacetamido )-2-d eoxy-o-gala ctopyranoses (IV and V), a mixture of the anomeric 1,3,5,6-te tra-0-acetyl-2- -(N-acetylacetamido) -2- deoxy-o-galactofuranoses (VII) and 1,4,6 - -tri -O-acetyl-2-(N-acetylacetamido)-2 ,3-dideoxy-o-threo-hex-2-enopyranose (X) . The anomeric 2-acetamido-1,3,4,6 -tetra-O-acetyl-2- -deo xy-n-galactopyranoses (VI) were also d etected ; they may be primary products or artifacts arising from IV and V by spontaneous de-N-acetylation in the course of the chromatography w hich was used

3,4,6-Tri-O-acetyl-2-(N-acetylacetamido )-1,2-dideoxy-o-Iyxohex- 1-enopyranose, an Acetamido-n-galactal Derivative, and the Mechanism of its Formation from 2-Acetamido-2-deoxy-D-galactose

The structure of an unsaturated amino sugar derivative, formed in low yield when 2-acetamido-2-deoxy-o-galactose _is treated with boiling isopropenyl acetate containing a trace of p-toluenesulfonic acid, and formulated as 1,4,6-tri-0-acetyl-2-(N-acetylacetamido)- 2,3-dideoxy-o-threo-hex-2-enopyranose(II) in an earlier publication, has been re-examined. Through a series of steps, including catalytic hydrogenation, the substance has been converted into a compound with an NMR spectrum which shows it to be 3,4,6-tri- 0-acetyl-2-(N -acetylbenzamido )-1,5-anhydro-2-deoxy-o-tali tol (X). This fact, together with a re-examination of its NMR spectrum, show the unsaturated compound to be 3,4,6-tri-0-acetyl-2-(N·· -acetylacetamido)-1,2-dideoxy-o-lyxo-hex-l-enopyranose (III), a derivative of 2-acetamido-o-galactal (VI). The yield of III from 2-acetamido-2-deoxy-o-galactose has been substantially improved through isolation of . 2-acetamido-1,3,4 , 6-tetra-0-acetyl-2-deoxy-~- o-galactopyranose (XIII) as an intermediate and III has been obtained in crystalline form. Evidence for the mechanism of its formation is presented

Allylic Displacement Reactions of a 2-Acetamido-D-glucal Derivative with Acids and Phenols

Fusion of 3,4,6-tri-O-acetyl-2-(N-acetylacetamido)-1,2-dideoxy- o-arabino-hex-1-enopyranose [I, 2-(N-acetylacetamido)-o-glucal triacetate] with various acids and phenols in the presence of. a trace of p-toluenesulfonic acid causes loss of the acetoxy group at C-3, shift of the double bond to the C-2-C-3 position, and entry of an acyloxy or aryloxy group at C-1 to give esters and glycosides, respectively, of 4,6-di-0-acetyl-2-(N-acetylacetamido)-2,3-dideoxy- a-o-erythro-hex-2-enopyranose (compounds III, V, VI, and VII). In each case, the main product is accompanied by 1,4,6-tri-O- acetyl-2- (N-acetylacetamido) -2,3-dideoxy-a-o-erythro-hex-2-enopyranose (IV), a substance which is found to be readily accessible through the deliberate rearrangement of I under acidic conditions. While IV reacts with benzoic acid when boiled in benzene solution containing hydrogen chloride, I is recovered unchanged after treatment in this fashion. On the basis of these facts, a mechanism for the acid-catalyzed reaction of I with carboxylic acids and phenols is proposed. An improved preparation of I from 2-acetamido-2-deoxy-omannose via 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-a-o-mannopyranose (II) is described. Phenyl 4,6-di-0-acetyl-2-(N -acetylacetamido )-2,3-dideoxy-a-D- eryth ro-hex-2-enopyranoside (VI) may be reduced by catalytic hydrogenation to the corresponding cyclohexyl glycoside (VIII), the double bond remaining unaffected

The Rearrangement Reaction of Some Acetylated Unsaturated 2-Acetamidoaldose Derivatives. Selective Removal of one N-Acetyl Group from 2-(N-acetylacetamido) Compounds

Two pairs of anomers, the l ,4,6-tri-0-acetyl-2-(N-acetylacetamido)- 2,3-dideoxy-o-hex-2-enopyranoses of the erythro- (II and III) and the threo- series (IV and VI) have been prepared and character; ized. The molecular conformation of these substances has been discussed on the basis of their NMR spectral characteristics. It is suggested that the a-anomers II and IV adopt the H~ conformation as the favorable one, while the B-anomers III and VI most probably tend to take a slightly modified H~ conformation. A convenient preparative method for selective removal of one N-acetyl group from 0-acetylated N-acetylacetamido compounds is described. The reaction can be carried out in aqueous dioxane solution at room temperature in the presence of an ammonium salt at pH ca. 9