Search

A series of five benzimidazole-based compounds were identified using a machine learning algorithm as potential inhibitors of the respiratory syncytial virus (RSV) fusion protein. These compounds were synthesized, and compound 2 in particular exhibited excellent in vitro potency with an EC(50) value of 5 nM. This new scaffold was then further refined leading to the identification of compound 44, which exhibited a 10-fold improvement in activity with an EC(50) value of 0.5 nM.

[Image: see text] Parkinson’s disease (PD) is a debilitating and common neurodegenerative disease. New insights implicating c-Abl activation as a driving force in PD have opened a new drug development avenue for PD treatment beyond the symptomatic relief by L-DOPA. BCR-Abl inhibitors, which include nilotinib and ponatinib, have been found to inhibit this process, and nilotinib has shown improvement in outcomes in a 12-patient, nonrandomized trial. However, nilotinib is a potent inhibitor of hERG, a cardiac K(+) channel whose inhibition increases risk of sudden death. We used our machine learning approach to predict novel molecules that would inhibit c-Abl while also having minimal liability against hERG. Of our six novel compounds tested, we identified two that had c-Abl potencies comparable to nilotinib, but with significantly improved profiles regarding the hERG channel. Our best compound exhibited a hERG IC(50) of 12.1 μM (compared to nilotinib with an IC(50) of 0.45 μM and ponatinib with IC(50) of 0.767 μM). This work is a step forward for a machine learning enabled, multiparameter optimization of a chemical space and represents a significant advance in the development of novel Parkinson’s therapies.

Dietary reconstruction in vertebrates often relies on dental wear-based proxies. Although these proxies are widely applied, the contributions of physical and mechanical processes leading to meso- and microwear are still unclear. We tested their correlation using sheep (Ovis aries, n = 39) fed diets of varying abrasiveness for 17 months as a model. Volumetric crown tissue loss, mesowear change and dental microwear texture analysis (DMTA) were all applied to the same teeth. We hereby correlate: (i) 46 DMTA parameters with each other, for the maxillary molars (M1, M2, M3), and the second mandibular molar (m2); (ii) 10 mesowear variables to each other and to DMTA for M1, M2, M3 and m2; and (iii) volumetric crown tissue loss to mesowear and DMTA for M2. As expected, many DMTA parameters correlated strongly with each other, supporting the application of reduced parameter sets in future studies. Correlation results showed only few DMTA parameters correlated with volumetric tissue change and even less so with mesowear variables, with no correlation between mesowear and volumetric tissue change. These findings caution against interpreting DMTA and mesowear patterns in terms of actual tissue removal until these dental wear processes can be better understood at microscopic and macroscopic levels.

Dental microwear texture analysis (DMTA) is widely used for diet inferences in extant and extinct vertebrates. Often, a reference tooth position is analysed in extant specimens, while isolated teeth are lumped together in fossil datasets. It is therefore important to test whether dental microwear texture (DMT) is tooth position specific and, if so, what causes the differences in wear. Here, we present results from controlled feeding experiments with 72 guinea pigs, which received either fresh or dried natural plant diets of different phytolith content (lucerne, grass, bamboo) or pelleted diets with and without mineral abrasives (frequently encountered by herbivorous mammals in natural habitats). We tested for gradients in dental microwear texture along the upper cheek tooth row. Regardless of abrasive content, guinea pigs on pelleted diets displayed an increase in surface roughness along the tooth row, indicating that posterior tooth positions experience more wear compared with anterior teeth. Guinea pigs feedings on plants of low phytolith content and low abrasiveness (fresh and dry lucerne, fresh grass) showed almost no DMT differences between tooth positions, while individuals feeding on more abrasive plants (dry grass, fresh and dry bamboo) showed a gradient of decreasing surface roughness along the tooth row. We suggest that plant feeding involves continuous intake and comminution by grinding, resulting in posterior tooth positions mainly processing food already partly comminuted and moistened. Pelleted diets require crushing, which exerts higher loads, especially on posterior tooth positions, where bite forces are highest. These differences in chewing behaviour result in opposing wear gradients for plant versus pelleted diets.

Dental microwear texture analysis (DMTA) is a common wear proxy using dental wear features to reconstruct diet in extant and extinct taxa. Dietary reconstructions of extinct species can be biased due to post-mortem mechanical modification of the dental surface. These post-mortem surface alterations can be caused by material loss after death, or as the result of burial, excavation, or preparation processes. In this study, we explore post-mortem surface alterations that occur during excavation, preparation, and conservation processes. We present a first general overview of unsuitable and suspicious dental surface scans and describe them both qualitatively and quantitatively using dental microwear texture (DMT) parameters. Finally, we compare these taphonomically altered surfaces to dental surfaces formed only by contact with a natural, ingested diet. We show that non-ingesta-related surfaces vary widely in morphologies. While some altered surfaces such as large post-mortem scratches or cracks in the enamel are easy to distinguish from ante-mortem ingesta-related wear features, others, such as remaining varnish covering the dental surface, are more obscure. The compiled surface defects dataset reveals that post-mortem altered surfaces often overlap with the parameter space of ingesta-related dental surfaces, but usually also include outliers with extreme values. To best identify dental surfaces with strong post-mortem alteration, we suggest using quantitative thresholds for frequently used DMT parameters for ingesta-related enamel surfaces based on literature values. However, with sufficient training and a reference database, these altered surfaces are detectable by an experienced user. Here we have compiled a first visual database of non-ingesta-related dental wear to help DMTA users identify these features and improve future DMTA studies.

Journal of structural biology 213(1), 107658 (1-12) (2021). doi:10.1016/j.jsb.2020.107658, Mammalian teeth have to sustain repetitive and high chewing loads without failure. Key to this capability is the periodontal ligament (PDL), a connective tissue containing a collagenous fibre network which connects the tooth roots to the alveolar bone socket and which allows the teeth to move when loaded. It has been suggested that rodent molars under load experience a screw-like downward motion but it remains unclear whether this movement also occurs in primates. Here we use synchroton micro-computed tomography paired with an axial loading setup to investigate the form-function relationship between tooth movement and the morphology of the PDL space in a non-human primate, the mouse lemur (Microcebus murinus). The loading behavior of both mandibular and maxillary molars showed a three-dimensional movement with translational and rotational components, which pushes the tooth into the alveolar socket. Moreover, we found a non-uniform PDL thickness distribution and a gradual increase in volumetric proportion of the periodontal vasculature from cervical to apical. Our results suggest that the PDL morphology may optimize the three-dimensional tooth movement to avoid high stresses under loading., Published by Elsevier, San Diego, Calif.

Sharks are apex-predators that play an important role in past and present aquatic food webs. However, their diet - especially in extinct species - is often not well constrained. Dental microwear texture analysis (DMTA) has been successfully applied to reconstruct diet and feeding behaviours of different aquatic and terrestrial vertebrates. However, unlike in mammals, food-to-tooth contact in sharks is rather limited because only larger prey is manipulated before swallowing. Together with a fast tooth replacement rate, this reduces wear on individual teeth. Here, we present an explorative study of dental microwear texture on extant and extinct sharks to test whether ante-mortem wear is related to ingested diet or habitat preferences and resistant to post-mortem alteration processes. Shark teeth from 24 modern species and 12 fossil species from different localities were measured. As an additional comparison, extant shark teeth of Carcharhinus plumbeus were tumbled in sedimentwater suspensions to simulate post-mortem mechanical alteration by sediment transport. Only three of the twelve extant shark species with three or more specimens had significantly different dental surface textures. Furthermore, no clear relation between food or habitat preferences and ante-mortem dental wear features was detected for this sample set. Tumbling modern shark teeth with siliciclastic sediment of four different grain size fractions led to increasing complexity of the dental surface. Fossil specimens resemble these experimentally altered shark teeth more in complexity and roughness. Thus, fossil shark teeth seem to display either very different (e.g. harder) diet-related wear or a strong degree of post-mortem alteration. Based on our restricted sample size, dental wear of shark teeth does overall not seem to simply reflect dietary differences; hence, it is difficult to use DMTA as reliable dietary reconstruction, in either extant nor extinct sharks.

N-Methyl-d-aspartate receptors (NMDARs) are ionotropic ligand-gated glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system (CNS). Several neurological disorders may involve NMDAR hypofunction, which has driven therapeutic interest in positive allosteric modulators (PAMs) of NMDAR function. Here we describe modest changes to the tetrahydroisoquinoline scaffold of GluN2C/GluN2D-selective PAMs that expands activity to include GluN2A- and GluN2B-containing recombinant and synaptic NMDARs. These new analogues are distinct from GluN2C/GluN2D-selective compounds like (+)-(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ) by virtue of their subunit selectivity, molecular determinants of action, and allosteric regulation of agonist potency. The (S)-enantiomers of two analogues (EU1180-55, EU1180-154) showed activity at NMDARs containing all subunits (GluN2A, GluN2B, GluN2C, GluN2D), whereas the (R)-enantiomers were primarily active at GluN2C- and GluN2D-containing NMDARs. Determination of the actions of enantiomers on triheteromeric receptors confirms their unique pharmacology, with greater activity of (S) enantiomers at GluN2A/GluN2D and GluN2B/GluN2D subunit combinations than (R) enantiomers. Evaluation of the (S)-EU1180-55 and EU1180-154 response of chimeric kainate/NMDA receptors revealed structural determinants of action within the pore-forming region and associated linkers. Scanning mutagenesis identified structural determinants within the GluN1 pre-M1 and M1 regions that alter the activity of (S)-EU1180-55 but not (R)-EU1180-55. By contrast, mutations in pre-M1 and M1 regions of GluN2D perturb the actions of only the (R)-EU1180-55 but not the (S) enantiomer. Molecular modeling supports the idea that the (S) and (R) enantiomers interact distinctly with GluN1 and GluN2 pre-M1 regions, suggesting that two distinct sites exist for these NMDAR PAMs, each of which has different functional effects.

Dental microwear texture (DMT) analysis is commonly applied for dietary reconstruction of vertebrates. The temporal scale on which dietarily informative microscopic wear forms on enamel surfaces is crucial to infer dietary flexibility and seasonality. Microwear is assumed to form shortly before the individual's death, reflecting information pertaining to the last meals consumed (“last supper” effect). In primate feeding experiments, microwear features formed within hours, suggesting rates of turnover within one to two weeks. As DMT formation experiments testing the persistence of microwear three-dimensionally (textures) are still lacking, we test how quickly DMTs form and pre-existing ones are overwritten in a terminal feeding experiment with 72 rats. In two groups of 36, rats received either a standard pelleted diet or the same pelleted diet containing 4% loess, an aeolian, silt-sized sediment, for 24 consecutive days. Then 6 individuals from each group were sacrificed, while the rest (n=30) were switched to the diet they had not received before. On day 1, 2, 4, 8, 16, and 24 after the diet switch, 5 of the remaining individuals were sacrificed, creating a cohort of n=5 each for each time point. We applied DMT analysis on first and second upper molars. For upper second molars, rats show a subsequent change in DMT after the switch, with visible differences from day 2 on. On upper first molars, microwear textures were variable for individuals sacrificed directly after the initial 24-day feeding period, thus obscuring significant differences in diet-induced dental wear. We find turnover faster and more pronounced when switching from loess-containing to standard pellet as compared to the opposite switch. The trend for either decreasing or increasing parameter values after the diet switch approaches a plateau between 16 and 24days for many DMT parameters, suggesting that, under these experimental conditions, the “last supper” effect needs at least two weeks to overwrite previous DMT patterns.

A herbivore's diet can affect its teeth by causing different types of wear. Browsers typically have sharper, higher cusps, while grazers show lower, blunter cusps, presumably due to the more abrasive nature of their diet. On the macroscopic scale, this allows the reconstruction of herbivore diets based on the shape of the tooth's profile, using the mesowear method. However, the timeframe involved in constituting a stable dietary signal represented by mesowear has not been precisely defined. To obtain a more precise delimitation of this timeframe, sheep (Ovis aries, n = 39) were fed pelleted diets containing external abrasives of different sizes (⌀ 4 μm, ⌀ 50 μm, and ⌀ 130 μm), and concentrations (4%, or 8%) for 17 months. Mesowear was scored on the skulls at the end of the experiment, as well as on computer-tomographic scans and on resin casts of the teeth taken at different timepoints along the experiment. These datasets were compared, and changes in score were calculated using the CT and cast data from the beginning and end of the experiment. Overall, even though a visual trend appeared of more wear on higher abrasion diets, it was of an extremely small magnitude, and the dietary effect on the mesowear scores or the change of the mesowear scores in these animals was never significant. This leads us to conclude that, at least in small ruminants, mesowear is more of a general signal than a seasonal one, and needs to be considered as such for tooth wear-based palaeodietary reconstructions. Experiments with natural forages are required to corroborate this conclusion.

One reason for the mammalian clade’s success is the evolutionary diversity of their teeth. In herbivores, this is represented by high‐crowned teeth evolved to compensate for wear caused by dietary abrasives like phytoliths and grit. Exactly how dietary abrasives wear teeth is still not understood completely. We fed four different pelleted diets of increasing abrasiveness (L: Lucerne; G: grass; GR: grass and rice husks; GRS: grass, rice husks, and sand) to four groups of a total of 28 adult goats, all with completely erupted third molars, over a six‐month period. Tooth morphology was captured by medical computed tomography scans at the beginning and end of the controlled feeding experiment, and separation lines between the crown and root segments were defined in the upper right second molar (M2), to gauge absolute wear. Using bootstrapping, significant differences in volume loss between diets L/G and GR/GRS were detected. A small but nevertheless consistent volume gain was noted in the roots, and there was a significant, positive correlation between crown volume loss and root volume gain. This growth could possibly be attributed to the well‐known process of cementum deposition and its relation with a putative feedback mechanism, in place to attenuate wear caused by abrasive diets.

A new study by Fraser et al (2018) urges the use of phylogenetic comparative methods, whenever possible, in analyses of mammalian tooth wear. We are concerned about this for two reasons. First, this recommendation may mislead the research community into thinking that phylogenetic signal is an artifact of some sort rather than a fundamental outcome of the evolutionary process. Secondly, this recommendation may set a precedent for editors and reviewers to enforce phylogenetic adjustment where it may unnecessarily weaken or even directionally alter the results, shifting the emphasis of analysis from common patterns manifested by large clades to rare cases.

Grasses are an important part of the forage of many herbivorous mammals and their phytoliths have long been regarded as the most important agent of tooth wear. Recent work has challenged this “paradigm” in finding evidence 1. of native phytoliths to be much softer then tooth enamel and 2. indicating, that phytolith hardness is highly variable, 3. prone to methodology and 4. not easy to be related to habitat conditions. We conduct controlled silica-cultivations measuring SiO2 content in the common forage grass Themeda triandra. Phytoliths are extracted natively, and nano-indentation values are measured. Phytolith hardness in Themeda triandra is found to be independent of silicate availability in the substrate. We further investigate the phytolith ultrastructure of Hordeum vulgare phytoliths. Phytoliths are shown to be an anisotropic composite of at least 3 components, silica bodies, inter-body matrix (both mineralised) and globular inclusions (likely non-mineralised). It can be argued, that indentation will be largely influenced by the heterogeneity of the structure and thus nano-indentation measurements will largely reflect the matrix and its mechanical properties but not necessarily the silicate bodies, which make up the vast majority of a phytolith.

Feeding practice in herbivorous mammals can impact their dental wear, due to excessive or irregular abrasion. Previous studies indicated that browsing species display more wear when kept in zoos compared to natural habitats. Comparable analyses in tapirs do not exist, as their dental anatomy and chewing kinematics are assumed to prevent the use of macroscopic wear proxies such as mesowear. We aimed at describing tapir chewing, dental anatomy and wear, to develop a system allowing comparison of free-ranging and captive specimens even in the absence of known age. Video analyses suggest that in contrast to other perissodactyls, tapirs have an orthal (and no lateral) chewing movement. Analysing cheek teeth from 74 museum specimens, we quantified dental anatomy, determined the sequence of dental wear along the tooth row, and established several morphometric measures of wear. In doing so, we showcase that tapir maxillary teeth distinctively change their morphology during wear, developing a height differential between less worn buccal and more worn lingual cusps, and that quantitative wear corresponds to the eruption sequence. We demonstrate that mesowear scoring shows a stable signal during initial wear stages but results in a rather high mesowear score compared to other browsing herbivores. Zoo specimens had lesser or equal mesowear scores as specimens from the wild; additionally, for the same level of third molar wear, premolars and other molars of zoo specimens showed similar or less wear compared specimens from the wild. While this might be due to the traditional use of non-roughage diet items in zoo tapirs, these results indicate that in contrast to the situation in other browsers, excessive tooth wear appears to be no relevant concern in ex situ tapir management.

External abrasives ingested along with the herbivore diet are considered main contributors to dental wear, though how the different sizes and concentrations of these abrasives influence wear remains unclear. Dental microwear texture analysis (DMTA) is an established method for dietary reconstruction which describes a tooth9s surface topography on a micrometre scale. The method has yielded conflicting results as to the effect of external abrasives. In the present study, a feeding experiment was performed on sheep (Ovis aries) fed seven diets of different abrasiveness. Our aim was to discern the individual effects of size (4, 50 and 130 µm) and concentration (0%, 4% and 8% of dry matter) of abrasives on dental wear, applying DMTA to four tooth positions. Microwear textures differed between individual teeth, but surprisingly, showed no gradient along the molar tooth row, and the strongest differentiation of experimental groups was achieved when combining data of all maxillary molars. Overall, a pattern of increasing height, volume and complexity of the tooth9s microscopic surface appeared with increasing size of dietary abrasives, and when compared with the control, the small abrasive diets showed a polishing effect. The results indicate that the size of dietary abrasives is more important for dental microwear texture traces than their concentration, and that different sizes can have opposing effects on the dietary signal. The latter finding possibly explains conflicting evidence from previous experimental DMTA applications. Further exploration is required to understand whether and how microscopic traces created by abrasives translate quantitatively to tissue loss.

There is an ongoing discourse about whether or not external abrasives influence the microscopic wear in herbivore teeth, including a statement that “dust does not matter”. We submitted the maxillary and mandibular second molar of 28 goats (Capra aegagrus hircus) to dental microwear texture analysis (DMTA). The study animals were divided into four groups, which received diets of increasing phytolith-based abrasiveness (L: lucerne based pellets, very low phytolith abrasion diet, acting as control; G: grass-based pellets, medium abrasive phytolith diet; GR: grass and rice husk pellets, high abrasion phytolith diet), or a diet with added external abrasives (GRS: the GR diet with addition of large-grained sand as source of external abrasives), for 6 months. Generally, the three diets without sand (L, G, GR) were ranked in the expected sequence by DMTA parameters. For some parameters, in particular those relating to area, complexity, peak sharpness and plateau size of the enamel surface, diet GRS differed from diet GR, whereas the two were not distinct in other parameters, mostly relating to direction, height or volume. Additionally, diets triggered different patterns on the maxillary or mandibular molar for several parameters. For some DMTA parameters, the range covered in the experimental goats corresponded to that observed in free-ranging browsing giraffe (Giraffa camelopardalis) and grazing wildebeest (Connochaetes taurinus), with goats receiving diet L resembling the giraffe, while the other diets G, GR and GRS more resembled the wildebeest. However, the previously reported mesowear in the goats did not cover the browser-grazer range, and DMTA measurements showed no correlation to the development of mesowear scores or measures of absolute tissue loss in the same animals. In summary, the results confirm DMTA measurements as generally recording properties related to both internal and external abrasives, but also indicate that our understanding of how DMTA characteristics actually originate, and how they relate to other proxies of dental wear, is still very limited.

An on-going debate concerning the dietary adaptations of archaic hominins and early Homo has been fuelled by contradictory inferences obtained using different methodologies. This work presents an extensive comparative sample of 30 extant primate species that was assembled to perform a morpho-functional comparison of these taxa with 12 models corresponding to eight fossil hominin species. Finite Element Analysis and Geometric Morphometrics were employed to analyse chewing biomechanics and mandible morphology to, firstly, establish the variation of this clade, secondly, relate stress and shape variables, and finally, to classify fossil individuals into broad ingesta related hardness categories using a support vector machine algorithm. Our results suggest that some hominins previously assigned as hard food consumers (e.g. the members of the Paranthropus clade) in fact seem to rely more strongly on soft foods, which is consistent with most recent studies using either microwear or stable isotope analyses. By analysing morphometric and stress results in the context of the comparative framework, we conclude that in the hominin clade there were probably no hard-food specialists. Nonetheless, the biomechanical ability to comminute harder items, if required as fallback option, adds to their strategy of increased flexibility.

Food processing wears down teeth, thus affecting tooth functionality and evolutionary success. Other than intrinsic silica phytoliths, extrinsic mineral dust/grit adhering to plants causes tooth wear in mammalian herbivores. Dental microwear texture analysis (DMTA) is widely applied to infer diet from microscopic dental wear traces. The relationship between external abrasives and dental microwear texture (DMT) formation remains elusive. Feeding experiments with sheep have shown negligible effects of dust-laden grass and browse, suggesting that intrinsic properties of plants are more important. Here, we explore the effect of clay- to sand-sized mineral abrasives (quartz, volcanic ash, loess, kaolin) on DMT in a controlled feeding experiment with guinea pigs. By adding 1, 4, 5, or 8% mineral abrasives to a pelleted base diet, we test for the effect of particle size, shape, and amount on DMT. Wear by fine-grained quartz (>5/ abrasive-free control diet. Fine silt-sized quartz (∼5 μm) results in higher surface anisotropy and lower roughness (polishing effect). Coarse-grained volcanic ash leads to significantly higher complexity, while fine sands (130 to 166 μm) result in significantly higher roughness. Complexity and roughness values exceed those from feeding experiments with guinea pigs who received plants with different phytolith content. Our results highlight that large (>95-μm) external silicate abrasives lead to distinct microscopic wear with higher roughness and complexity than caused bymineral abrasive-free herbivorous diets. Hence, high loads of mineral dust and grit in natural diets might be identified by DMTA, also in the fossil record.

More than half of new drugs entering the German healthcare system have not been shown to add benefit. Beate Wieseler and colleagues argue that international drug development processes and policies are responsible and must be reformed

Machine learning continues to make strident advances in the prediction of desired properties concerning drug development. Problematically, the efficacy of machine learning in these arenas is reliant upon highly accurate and abundant data. These two limitations, high accuracy and abundance, are often taken together; however, insight into the dataset accuracy limitation of contemporary machine learning algorithms may yield insight into whether non-bench experimental sources of data may be used to generate useful machine learning models where there is a paucity of experimental data. We took highly accurate data across six kinase types, one GPCR, one polymerase, a human protease, and HIV protease, and intentionally introduced error at varying population proportions in the datasets for each target. With the generated error in the data, we explored how the retrospective accuracy of a Naïve Bayes Network, a Random Forest Model, and a Probabilistic Neural Network model decayed as a function of error. Additionally, we explored the ability of a training dataset with an error profile resembling that produced by the Free Energy Perturbation method (FEP+) to generate machine learning models with useful retrospective capabilities. The categorical error tolerance was quite high for a Naïve Bayes Network algorithm averaging 39% error in the training set required to lose predictivity on the test set. Additionally, a Random Forest tolerated a significant degree of categorical error introduced into the training set with an average error of 29% required to lose predictivity. However, we found the Probabilistic Neural Network algorithm did not tolerate as much categorical error requiring an average of 20% error to lose predictivity. Finally, we found that a Naïve Bayes Network and a Random Forest could both use datasets with an error profile resembling that of FEP+. This work demonstrates that computational methods of known error distribution like FEP+ may be useful in generating machine learning models not based on extensive and expensive in vitro-generated datasets.

Zinc porphyrin-functionalized fullerene [C60] derivatives have been synthesized and usedto prepare titania-based composites. The electrochemical properties and HOMO andLUMO levels of the photosensitizers were determined by electrochemical measurements.Raman and IR techniques were used to study chemical groups present on the titaniasurface. Absorption properties of the composites were measured in the solid state bydiffuse reflectance UV-Vis spectra (DRS).

In the fossil record, teeth are often all that remains of a fossil organism. Dental microwear texture analysis (DMTA) is a common proxy for diet using dental wear features at the μm-scale, enabling comparative and quantitative assessments of various feeding traits in extant and extinct species. In extinct species, original diet-related dental wear features may be overprinted by post-mortem alteration including fluvial transport. Here we experimentally investigate the effects of mechanical alteration on diet-related 3D enamel surface texture (3DST) patterns of different mammal teeth. Post canine teeth of Equus sp., Capreolus capreolus and Otomys sp. are tumbled in sediment-water suspensions using three different grain size fractions of sand. The 3DST of the enamel surfaces are measured prior to and after each tumbling interval and characterised using ISO normed surface texture and SSFA parameters. In all species, we find several parameters to be almost unaffected by tumbling (stable parameters), while other parameters show inconsistent-directional shifts (unstable parameters). For Otomys, all three sediment grain size fractions result in abrasion of peaks and a reduction of overall surface roughness. For Equus, tumbling results in visible abrasive changes in the original wear patterns and the introduction of new wear features. Capreolus capreolus shows high variability in surface texture patterns prior to and after the experiment, hence we see ambiguous trends for changes in parameter values. However, even after 336 h of tumbling the browsing C. capreolus can still be distinguished from the grazing Equus sp. Thus, biostratinomy may potentially modify diet-related 3DST causing non-systematic bias via mechanical abrasion, which is related to sediment grain size, duration of transport and geometry of teeth. However, the original diet-related 3DST is still preserved and a more prominent characteristic in DMT than the experimentally induced diagenetic alteration.

Dietary reconstruction in vertebrates often relies on dental wear-based proxies. Although these proxies are widely applied, the contributions of physical and mechanical processes leading to meso- and microwear are still unclear. We tested their correlation using sheep ( Ovis aries , n = 39) fed diets of varying abrasiveness for 17 months as a model. Volumetric crown tissue loss, mesowear change and dental microwear texture analysis (DMTA) were all applied to the same teeth. We hereby correlate: (i) 46 DMTA parameters with each other, for the maxillary molars (M1, M2, M3), and the second mandibular molar (m2); (ii) 10 mesowear variables to each other and to DMTA for M1, M2, M3 and m2; and (iii) volumetric crown tissue loss to mesowear and DMTA for M2. As expected, many DMTA parameters correlated strongly with each other, supporting the application of reduced parameter sets in future studies. Correlation results showed only few DMTA parameters correlated with volumetric tissue change and even less so with mesowear variables, with no correlation between mesowear and volumetric tissue change. These findings caution against interpreting DMTA and mesowear patterns in terms of actual tissue removal until these dental wear processes can be better understood at microscopic and macroscopic levels.

Altres ajuts: "Beatriu de Pinos" 2014 - BP-A 00048 There is considerable debate regarding whether mandibular morphology in ungulates primarily reflects phylogenetic affinities or adaptation to specific diet. In an effort to help resolve this debate, we use three-dimensional finite element analysis (FEA) to assess the biomechanical performance of mandibles in eleven ungulate taxa with well-established but distinct dietary preferences. We found notable differences in the magnitude and the distribution of von Mises stress between Artiodactyla and Perissodactyla, with the latter displaying lower overall stress values. Additionally, within the order Artiodactyla the suborders Ruminantia and Tylopoda showed further distinctive stress patterns. Our data suggest that a strong phylogenetic signal can be detected in biomechanical performance of the ungulate mandible. In general, Perissodactyla have stiffer mandibles than Artiodactyla. This difference is more evident between Perissodactyla and ruminant species. Perissodactyla likely rely more heavily on thoroughly chewing their food upon initial ingestion, which demands higher bite forces and greater stress resistance, while ruminants shift comminution to a later state (rumination) where less mechanical effort is required by the jaw to obtain sufficient disintegration. We therefore suggest that ruminants can afford to chew sloppily regardless of ingesta, while hindgut fermenters cannot. Additionally, our data support a secondary degree of adaptation towards specific diet. We find that mandibular morphologies reflect the masticatory demands of specific ingesta within the orders Artiodactyla and Perissodactyla. Of particular note, stress patterns in the white rhinoceros (C. simum) look more like those of a general grazer than like other rhinoceros' taxa. Similarly, the camelids (Tylopoda) appear to occupy an intermediate position in the stress patterns, which reflects the more ancestral ruminating system of the Tylopoda.

Dental mesowear is applied as a proxy to determine the general diet of mammalian herbivores based on tooth-cusp shape and occlusal relief. Low, blunt cusps are considered typical of grazers and high, sharp cusps typical of browsers. However, how internal or external abrasives impact mesowear, and the time frame the wear signature takes to develop, still need to be explored. Four different pelleted diets of increasing abrasiveness (lucerne, grass, grass and rice husks, and grass, rice husks and sand) were fed to four groups of a total of 28 adult goats in a controlled feeding experiment over a 6-month period. Tooth morphology was captured by medical CT scans at the beginning and end of the experiment. These scans, as well as the crania obtained post mortem, were scored using the mesowear method. Comparisons between diet groups showed few significant differences after 6 months, irrespective of whether CT scans or the real teeth were scored. Only when assessing the difference in signal between the beginning and the end of the experiment did relevant, significant diet-specific effects emerge. Diets containing lower phytolith content caused a more pronounced change in mesowear towards sharper cusps/higher reliefs, while the feed containing sand did not result in more extreme changes in mesowear when compared with the same feed without sand. Our experiment suggests that the formation of a stable and hence reliable mesowear signal requires more time to develop than 6 months.

Bis 2020 werden mehr als 50 Milliarden Gerate mit dem Internet verbunden sein. Mit Hilfe Cyber-Physikalischer Systeme und digitaler Zwillinge, die die reale mit der virtuellen Welt verbinden, konnen Prozesse automatisiert und wertvolle Erkenntnisse gewonnen werden. Dies ermoglicht neue Geschaftsmodelle auf Basis intelligenter Produkte und Dienstleistungen.

At the beginning of 2011, the early benefit assessment of new drugs was introduced in Germany with the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G‐BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this type of assessment, which examines whether a new drug shows an added benefit (a positive patient‐relevant treatment effect) over the current standard therapy. IQWiG is required to assess the extent of added benefit on the basis of a dossier submitted by the pharmaceutical company responsible. In this context, IQWiG was faced with the task of developing a transparent and plausible approach for operationalizing how to determine the extent of added benefit. In the case of an added benefit, the law specifies three main extent categories (minor, considerable, major). To restrict value judgements to a minimum in the first stage of the assessment process, an explicit and abstract operationalization was needed. The present paper is limited to the situation of binary data (analysis of 2 × 2 tables), using the relative risk as an effect measure. For the treatment effect to be classified as a minor, considerable, or major added benefit, the methodological approach stipulates that the (two‐sided) 95% confidence interval of the effect must exceed a specified distance to the zero effect. In summary, we assume that our approach provides a robust, transparent, and thus predictable foundation to determine minor, considerable, and major treatment effects on binary outcomes in the early benefit assessment of new drugs in Germany. After a decision on the added benefit of a new drug by G‐BA, the classification of added benefit is used to inform pricing negotiations between the umbrella organization of statutory health insurance and the pharmaceutical companies.

Reasons for performing study: Captive breeding has played a crucial role in the conservation of threatened equid species. Grazing ruminants and rhinoceros in captivity have less abrasion-dominated tooth wear than their free-ranging conspecifics, with potential negative consequences for their health. However, a similar study on wild equids in captivity is missing. Objectives: The aim was to establish if different tooth wear patterns are exhibited by free-ranging and captive equids. Study design: Cross-sectional study of museum specimens comparing free-ranging and captive equids. Methods: Dental casts of maxillary cheek teeth of 228 museum specimens (122 from free-ranging and 106 from captive individuals) of 7 wild equid species were analysed using the extended mesowear method. Although teeth showing specific abnormalities were not scored, the presence of focal overgrowths (hooks) of the rostral premolars (106, 206) was recorded. Results: Captive Equus ferus przewalskii, E. grevyi, E. hemionus, E. quagga boehmi and E. zebra hartmannae have less abrasion-dominated tooth wear on their premolars than their free-ranging conspecifics (P

A method capable of identifying novel synthetic targets for small molecule lead optimization has been developed. The FRESH (FRagment-based Exploitation of modular Synthesis by vHTS) approach relies on a multistep synthetic route to a target series of compounds devised by a close collaboration between synthetic and computational chemists. It combines compound library generation, quantitative structure-acitvity relationship construction, fragment processing, virtual high throughput screening and display of results within the Pipeline Pilot framework. Outcomes enumerate tailored selection of novel synthetic targets with improved potency and optimized physical properties for an emerging compound series. To validate the application of FRESH, three retrospective case studies have been performed to pinpoint reported potent analogues. One prospective case study was performed to demonstrate that FRESH is able to capture additional potent analogues.