Modeling enamel matrix secretion in mammalian teeth

The most mineralized tissue of the mammalian body is tooth enamel. Especially in species with thick enamel, three-dimensional (3D) tomography data has shown that the distribution of enamel varies across the occlusal surface of the tooth crown. Differences in enamel thickness among species and within the tooth crown have been used to examine taxonomic affiliations, life history, and functional properties of teeth. Before becoming fully mineralized, enamel matrix is secreted on the top of a dentine template, and it remains to be explored how matrix thickness is spatially regulated. To provide a predictive framework to examine enamel distribution, we introduce a computational model of enamel matrix secretion that maps the dentine topography to the enamel surface topography. Starting from empirical enamel-dentine junctions, enamel matrix deposition is modeled as a diffusion-limited free boundary problem. Using laboratory microCT and synchrotron tomographic data of pig molars that have markedly different dentine and enamel surface topographies, we show how diffusion-limited matrix deposition accounts for both the process of matrix secretion and the final enamel distribution. Simulations reveal how concave and convex dentine features have distinct effects on enamel surface, thereby explaining why the enamel surface is not a straightforward extrapolation of the dentine template. Human and orangutan molar simulations show that even subtle variation in dentine topography can be mapped to the enamel surface features. Mechanistic models of extracellular matrix deposition can be used to predict occlusal morphologies of teeth. Author summary Teeth of most mammals are covered by a layer of highly mineralized enamel that cannot be replaced or repaired. The enamel layer is not uniform over the underlying dentine, and spatial regulation of enamel formation is critical for making a functional tooth. To explore which kind of mechanisms could underlie the complex patterns of enamel distribution, we present a computational model. Starting from tomography-imaged teeth from which enamel has been digitally removed, enamel is restored on dentine surfaces by simulating diffusion-limited secretion of enamel matrix. Our simulations show how the combination of subtle features of dentine and diffusion-limited secretion of the enamel matrix can substantially increase the complexity of the enamel surface. We propose that the strength of the diffusion-limited process is a key factor in determining enamel distribution among mammalian species.Peer reviewe

Substantial Fat Loss in Physique Competitors Is Characterized by Increased Levels of Bile Acids, Very-Long Chain Fatty Acids, and Oxylipins

Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 ± 3.1 weeks) leading to substantial fat mass loss of 52% (−7.9 ± 1.5 kg) and low body fat (12.7 ± 4.1%), the liquid chromatography-mass spectrometry-based metabolic signature of 24 previously young, healthy, and normal weight female physique athletes was investigated. We observed uniform increases (FDR < 0.05) in bile acids, very-long-chain free fatty acids (FFA), and oxylipins, together with reductions in unsaturated FFAs after weight loss. These widespread changes, especially in the bile acid profile, were most strongly explained (FDR < 0.05) by changes in android (visceral) fat mass. The reported changes did not persist, as all of them were reversed after the subsequent voluntary weight regain period (18.4 ± 2.9 weeks) and were unchanged in non-dieting controls (n = 16). Overall, we suggest that the reported changes in FFA, bile acid, and oxylipin profiles reflect metabolic adaptation to very low levels of fat mass after prolonged periods of intense exercise and low-energy availability. However, the effects of the aforementioned metabolome subclass alteration on metabolic homeostasis remain controversial, and more studies are warranted to unravel the complex physiology and potentially associated health implications. In the end, our study reinforced the view that transient weight loss seems to have little to no long-lasting molecular and physiological effects

Substantial Fat Loss in Physique Competitors Is Characterized by Increased Levels of Bile Acids, Very-Long Chain Fatty Acids, and Oxylipins

Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 ± 3.1 weeks) leading to substantial fat mass loss of 52% (−7.9 ± 1.5 kg) and low body fat (12.7 ± 4.1%), the liquid chromatography-mass spectrometry-based metabolic signature of 24 previously young, healthy, and normal weight female physique athletes was investigated. We observed uniform increases (FDR < 0.05) in bile acids, very-long-chain free fatty acids (FFA), and oxylipins, together with reductions in unsaturated FFAs after weight loss. These widespread changes, especially in the bile acid profile, were most strongly explained (FDR < 0.05) by changes in android (visceral) fat mass. The reported changes did not persist, as all of them were reversed after the subsequent voluntary weight regain period (18.4 ± 2.9 weeks) and were unchanged in non-dieting controls (n = 16). Overall, we suggest that the reported changes in FFA, bile acid, and oxylipin profiles reflect metabolic adaptation to very low levels of fat mass after prolonged periods of intense exercise and low-energy availability. However, the effects of the aforementioned metabolome subclass alteration on metabolic homeostasis remain controversial, and more studies are warranted to unravel the complex physiology and potentially associated health implications. In the end, our study reinforced the view that transient weight loss seems to have little to no long-lasting molecular and physiological effects

Substantial Fat Loss in Physique Competitors Is Characterized by Increased Levels of Bile Acids, Very-Long Chain Fatty Acids, and Oxylipins

Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 +/- 3.1 weeks) leading to substantial fat mass loss of 52% (-7.9 +/- 1.5 kg) and low body fat (12.7 +/- 4.1%), the liquid chromatography-mass spectrometry-based metabolic signature of 24 previously young, healthy, and normal weight female physique athletes was investigated. We observed uniform increases (FDR < 0.05) in bile acids, very-long-chain free fatty acids (FFA), and oxylipins, together with reductions in unsaturated FFAs after weight loss. These widespread changes, especially in the bile acid profile, were most strongly explained (FDR < 0.05) by changes in android (visceral) fat mass. The reported changes did not persist, as all of them were reversed after the subsequent voluntary weight regain period (18.4 +/- 2.9 weeks) and were unchanged in non-dieting controls (n = 16). Overall, we suggest that the reported changes in FFA, bile acid, and oxylipin profiles reflect metabolic adaptation to very low levels of fat mass after prolonged periods of intense exercise and low-energy availability. However, the effects of the aforementioned metabolome subclass alteration on metabolic homeostasis remain controversial, and more studies are warranted to unravel the complex physiology and potentially associated health implications. In the end, our study reinforced the view that transient weight loss seems to have little to no long-lasting molecular and physiological effects

Muscle activity and inactivity periods during normal daily life

Recent findings suggest that not only the lack of physical activity, but also prolonged times of sedentary behaviour where major locomotor muscles are inactive, significantly increase the risk of chronic diseases. The purpose of this study was to provide details of quadriceps and hamstring muscle inactivity and activity during normal daily life of ordinary people. Eighty-four volunteers (44 females, 40 males, 44.1&plusmn;17.3 years, 172.3&plusmn;6.1 cm, 70.1&plusmn;10.2 kg) were measured during normal daily life using shorts measuring muscle electromyographic (EMG) activity (recording time 11.3&plusmn;2.0 hours). EMG was normalized to isometric MVC (EMGMVC) during knee flexion and extension, and inactivity threshold of each muscle group was defined as 90% of EMG activity during standing (2.5&plusmn;1.7% of EMGMVC). During normal daily life the average EMG amplitude was 4.0&plusmn;2.6% and average activity burst amplitude was 5.8&plusmn;3.4% of EMGMVC (mean duration of 1.4&plusmn;1.4 s) which is below the EMG level required for walking (5 km/h corresponding to EMG level of about 10% of EMGMVC). Using the proposed individual inactivity threshold, thigh muscles were inactive 67.5&plusmn;11.9% of the total recording time and the longest inactivity periods lasted for 13.9&plusmn;7.3 min (2.5&ndash;38.3 min). Women had more activity bursts and spent more time at intensities above 40% EMGMVC than men (p&lt;0.05). In conclusion, during normal daily life the locomotor muscles are inactive about 7.5 hours, and only a small fraction of muscle\u27s maximal voluntary activation capacity is used averaging only 4% of the maximal recruitment of the thigh muscles. Some daily non-exercise activities such as stair climbing produce much higher muscle activity levels than brisk walking, and replacing sitting by standing can considerably increase cumulative daily muscle activity

Biologisen kehityksen laskennallisesta mallintamisesta

This thesis considers the mathematical modeling of patterning and growth in biological systems. The fundamental objective is to build realistic, yet efficient and well-described mathematical models of morphogenesis to help understand not just the specific systems under study, but ultimately the evolutionary processes that sculpt the biological forms, from tissues to complete organs. Developmental mechanisms both guide and restrict the evolution of biological forms, and mathematical models provide a powerful tool to understand the role and significance of those restrictions. The first study considers the developmental mechanisms of evolutionary transitions in mammalian dentition. In the study, the development of mouse molars is experimentally controlled, and a smooth transition in tooth morphology is demonstrated in response to controlling a single signaling morphogen. The experimental results are plausibly recapitulated in a computational model of tooth development, which is implemented in a user-friendly interface with the aim of bridging the traditional gap between biologists doing the experiments and mathematicians building the models. The second study investigates the relation between size and spacing of the taste papillae in the mouse tongue. It is observed that experimentally controlling the FGF signaling changes the size but not the spacing of the taste papillae. Based on the results it is suggested that FGF signaling affects the extend of canonical Wnt signaling by changing the local diffusion of Wnt. Support for the hypothesis is obtained from simulations of a reaction-diffusion (Turing) model, where the activator morphogen diffusion constant is replaced with a non-linear function. In the third study, a mathematical model of tooth enamel formation is proposed. The model assumes that the process of laying down the enamel in teeth is limited by the diffusion of nutrients required by the secreting cells. Using computer simulations it is demonstrated how the model is capable of plausibly reproducing the enamel surface patterns on the top of thick enamel, resulting from the uneven surface of the underlying tooth structures. The fourth study considers the application of the Stokes equation for the simulation of tissue growth. The system is coupled with a reaction-diffusion system augmented with a differentiation mechanism to mimic the state-changes in cells, such as the establishment of signaling centers. An efficient numerical framework for solving the system in 3D is developed, and the implementation is validated using numerical tests with known solutions. To demonstrate the model dynamics, idealized tissue growth is simulated in scenarios with varying amounts of surface tension and incorporating non-homogeneous viscosity profiles.Tässä väitöskirjassa tarkastellaan biologisen kaavoituksen ja kasvun matemaattista mallinnusta. Perimmäisenä tavoitteena on rakentaa realistisia mutta tehokkaita matemaattisia malleja kuvaamaan sekä biologisten rakenteiden muodostumista että laajemmin evolutiivisia prosesseja, jotka muovaavat noita rakenteita. Kehitykselliset mekanismit sekä ohjaavat että rajoittavat biologisten rakenteiden evoluutiota, ja matemaattiset mallit tarjoavat tehokkaan työkalun noiden rajoitusten ymmärtämiseen. Ensimmäisessä tutkimuksessa tarkastellaan nisäkäshampaiden evolutiivisten muutoksien kehitysmekanismeja. Hiiren hampaan kehitystä muunnellaan kokeellisesti, ja tuloksena pystytään tuottamaan tasaisia siirtymiä eri muotojen välillä. Kokeelliset tulokset pystytään toistamaan uskottavasti hampaan kehitystä kuvaavan tietokonemallin avulla. Tietokonemalli on toteutettu käyttäjäystävälliseen käyttöliittymään, tavoitteena helpottaa poikkitieteellistä yhteistyötä biologien ja matemaatikkojen välillä. Toisessa tutkimuksessa tarkastellaan hiiren kielen makunystyjen koon ja etäisyyden välistä yhteyttä. Kokeissa havaitaan, että muuntelemalla FGF-signalointia systeemissä nystyjen koko muuttuu keskimääräisen etäisyyden säilyessä vakiona. Tulosten perusteella ehdotetaan, että FGF-signaali vaikuttaa Wnt-signaalin toimintaan muuttamalla Wnt:n paikallista diffuusiota geenitranskription sijaan. Hypoteesille saadaan tukea tietokonemallista, jossa klassista reaktio-diffuusio (Turing) mallia laajennetaan korvaamalla diffuusiovakio epälineaarisella funktiolla. Kolmannessa tutkimuksessa esitetään hampaan kiilteen muodostumiselle matemaattinen malli, jossa kiilteen muodostumisen oletetaan olevan ravinnediffuusiorajoitteinen ilmiö. Tutkimuksessa osoitetaan, että malli kykenee toistamaan paksun kiilteen päällä esiintyvät rakennemuodot lähtien liikkeelle kiilteen alla olevista hampaan rakenteista. Neljännessä tutkimuksessa tarkastellaan Stokesin yhtälön soveltamista kudoksen kasvun mallintamiseen. Stokesin yhtälöstä käytetään laajempaa muotoa, jossa huomioidaan vaihteleva viskositeetti ja massalähteet. Systeemiin liitetään reaktio-diffuusio kaavoitusmekanismi, joka on laajennettu solujen erikoistumista kuvaavalla mekanismilla. Tutkimuksessa kehitetään tehokas numeerinen alusta ongelman ratkaisemiseksi, jonka tarkkuutta tutkitaan numeerisilla testeillä joiden ratkaisu tunnetaan. Mallin toimintaa esitellään kuvaamalla ideaalin kudoksen kasvua tilanteissa, joissa on vaihteleva pintajännite ja erilaisia viskositeettiprofiileja

Atorvastatin induces adrenal androgen downshift in men with prostate cancer: A post Hoc analysis of a pilot adaptive Randomised clinical trial

Background: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa. Methods: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms. Findings: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value <0.0001, median difference -342.5; 95% CI -505.23 – -188.98). In the prostatic tissue, atorvastatin was associated with plausible downshift in 11- ketodihydrotestosterone (placebo 25.0pM in 100 mg tissue/1 mL saline, atorvastatin 18.5pM in 100 mg tissue/1 mL saline, p-value 0.027, median difference -6.53; 95% CI -12.8 – -0.29); however, this association diminished after adjusting for multiple testing. No serious harms were reported. Interpretation: Atorvastatin was associated with adrenal androgen downshift in the serum and possibly in the prostate. The finding warrants further investigation whether atorvastatin could improve androgen deprivation therapy efficacy. Funding: Funded by grants from the Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital. Clinicaltrials.gov identifier: NCT01821404.Peer reviewe

Mechanical Constraint from Growing Jaw Facilitates Mammalian Dental Diversity

International audienc

Bracketing phenogenotypic limits of mammalian hybridization

An increasing number of mammalian species have been shown to have a history of hybridization and introgression based on genetic analyses. Only relatively few fossils, however, preserve genetic material, and morphology must be used to identify the species and determine whether morphologically intermediate fossils could represent hybrids. Because dental and cranial fossils are typically the key body parts studied in mammalian palaeontology, here we bracket the potential for phenotypically extreme hybridizations by examining uniquely preserved cranio-dental material of a captive hybrid between grey and ringed seals. We analysed how distinct these species are genetically and morphologically, how easy it is to identify the hybrids using morphology and whether comparable hybridizations happen in the wild. We show that the genetic distance between these species is more than twice the modern human–Neanderthal distance, but still within that of morphologically similar species pairs known to hybridize. By contrast, morphological and developmental analyses show grey and ringed seals to be highly disparate, and that the hybrid is a predictable intermediate. Genetic analyses of the parent populations reveal introgression in the wild, suggesting that grey–ringed seal hybridization is not limited to captivity. Taken together, we postulate that there is considerable potential for mammalian hybridization between phenotypically disparate taxa.Peer reviewe