Colibactin mutational signatures in NTHL1 tumor syndrome and MUTYH associated polyposis patients.

Polyketide synthase (pks) island harboring Escherichia coli are, under the right circumstances, able to produce the genotoxin colibactin. Colibactin is a risk factor for the development of colorectal cancer and associated with mutational signatures SBS88 and ID18. This study explores colibactin-associated mutational signatures in biallelic NTHL1 and MUTYH patients. Targeted Next Generation Sequencing (NGS) was performed on colorectal adenomas and carcinomas of one biallelic NTHL and 12 biallelic MUTYH patients. Additional fecal metagenomics and genome sequencing followed by mutational signature analysis was conducted for the NTHL1 patient. Targeted NGS of the NTHL1 patient showed somatic APC variants fitting SBS88 which was confirmed using WGS. Furthermore, fecal metagenomics revealed pks genes. Also, in 1 out of 11 MUTYH patient a somatic variant was detected fitting SBS88. This report shows that colibactin may influence development of colorectal neoplasms in predisposed patients.

How feelings of unpleasantness develop during the progression of motion sickness symptoms.

To mitigate motion sickness in self-driving cars and virtual reality, one should be able to quantify its progression unambiguously. Self-report rating scales either focus on general feelings of unpleasantness or specific symptomatology. Although one generally feels worse as symptoms progress, there is anecdotal evidence suggesting a non-monotonic relationship between unpleasantness and symptomatology. This implies that individuals could (temporarily) feel better as symptoms progress, which could trouble an unambiguous measurement of motion sickness progression. Here we explicitly investigated the temporal development of both unpleasantness and symptomatology using subjective reports, as well as their mutual dependence using psychophysical scaling techniques. We found symptoms to manifest in a fixed order, while unpleasantness increased non-monotonically. Later manifesting symptoms were generally judged as more unpleasant, except for a reduction at the onset of nausea, which corresponded to feeling better. Although we cannot explicate the origin of this reduction, its existence is of importance to the quantification of motion sickness. Specifically, the reduction at nausea onset implies that rating how bad someone feels does not give you an answer to the question of how close someone is to the point of vomiting. We conclude that unpleasantness can unambiguously be inferred from symptomatology, but an ambiguity exists when inferring symptomatology from unpleasantness. These results speak in favor of rating symptomatology when prioritizing an unambiguous quantification of motion sickness progression.

A re-investigation of the role of utricular asymmetries in Space Motion Sickness.

During the first days of spaceflight, about 50-70% of the astronauts experience symptoms of Space Motion Sickness (SMS). It has been proposed that an asymmetry between the left and right otolith organs contributes to an astronaut's individual susceptibility. A recently developed test to measure unilateral utricular function enabled us to re-investigate this so-called otolith asymmetry hypothesis, while using the paradigm of sustained centrifugation as a ground based model for SMS. This latter paradigm has been shown to elicit symptoms similar to those of SMS and is referred to as Sickness Induced by Centrifugation (SIC). In 15 healthy subjects unilateral utricular function was assessed by recording ocular counter rolling during a unilateral centrifugation paradigm. In addition, saccular function was assessed by recording Vestibular Evoked Myogenic Potentials (VEMPs), and horizontal semicircular canal function was assessed using bithermal caloric stimulation. SIC-susceptible subjects showed a marginally higher degree of utricular asymmetry, utricular sensitivity and semicircular canal sensitivity (p < 0.1) than the non-susceptible group. Interestingly, a logistic regression model using both utricular and semicircular canal parameters led to a correct classification of 91% of the subjects. As such, these results suggest that otolith asymmetry is at most one factor - and not present in all susceptible subjects - in defining susceptibility to SMS and SIC. Both the utricular and the canal system might be involved as well.

A new model for utricular function testing using a sinusoidal translation profile during unilateral centrifugation.

The utricle plays an important role in orientation with respect to gravity. The unilateral centrifugation test allows a side-by-side investigation of both utricles. During this test, the subject is rotated about an earth-vertical axis at high rotation speeds (e.g. 400°/s) and translated along an interaural axis to consecutively align the axis of rotation with the left and the right utricle. A simple sinusoidal translation profile (0.013 Hz; amplitude = 4 cm) was chosen. The combined rotation and translation induces ocular counter rolling (OCR), which is measured using 3-D video-oculography. This OCR is the sum of the reflexes generated by both the semicircular canals and the utricles. In this paper, we present a new physiological model that decomposes this total OCR into a canal and a utricular contribution, modelled by a second-order transfer function and a combination of 2 sine functions, respectively. This model yields parameters such as canal gain, cupular and adaptation time constants and a velocity storage component for the canals. Utricular gain, bias, phase and the asymmetry between the left and the right utricle are characteristic parameters generated by the model for the utricles. The model is presented along with the results of 10 healthy subjects and 2 patients with a unilateral vestibular loss due to acoustic neuroma surgery to illustrate the effectiveness of the model.