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For the estimation and further optimization of the residual stress and distortion state in additively manufactured structures during and after the wire arc additive manufacturing (WAAM) process, thermomechanical simulation can be applied as a numerical tool. In addition to the detailed modelling of key process parameters, the used material model and material data have a major influence on the accuracy of the numerical analysis. The material behaviour, in particular the viscoplastic behaviour of the titanium alloy Ti-6Al-4 V which is commonly used in aerospace, is investigated within this work. An extensive material characterization of the viscoplastic material behaviour of the WAAM round specimen is carried out conducting low cycle fatigue (LCF) and complex low cycle fatigue (CLCF) tests in a wide temperature range. An elasto-viscoplastic Chaboche material model is parameterised, fitted, and validated to the experimental data in the investigated temperature range. Subsequently, the material model is implemented in the thermomechanical simulation of a representative, linear ten-layer WAAM structure. To finally determine the effect of the fitted material model on the estimation accuracy of residual stress and distortion, simulation results using the standard material model and the elaborated Chaboche model from this study are compared to experimental data in the substrate. The thermomechanical simulation with the Chaboche model reveals a better agreement with the experimental distortion and residual stress state, whereby the standard material model tends to an overestimation. The estimation accuracy with respect to the maximum distortion is improved from an error of 60% with the standard model to an acceptable error of about 6% using the elaborated model. Additionally, the estimated residual stress state shows a sound agreement to the experimental residual stress in the substrate.

Facial nerve paralysis or Bell's palsy have been suggested as possible consequences of SARS-CoV-2 infections, as well as possible side effects of COVID-19 vaccinations. Google Trends data have been used to evaluate worldwide levels of public awareness for these topics for pre- and post-pandemic years. The results demonstrate a relatively low public interest in facial nerve paralysis in comparison to other more common COVID-19 related topics. Some peaks of interest in Bell's palsy can most likely be explained as triggered by the media. Therefore, Google Trends has shown public's relatively low awareness of this rare neurological phenomenon during the pandemic.

Cardiac troponin I (cTnI) contains a N-terminal extension harboring protein kinase A targets (Ser23/24), which are phosphorylated during ß-adrenergic stimulation to increase cardiomyocyte relaxation rate. Here, we show that exon 3 ofTNNI3, encoding most of the cTnI N-terminal extension including Ser23/24, was pseudoexonized multiple times in shrews and moles to mimic Ser23/24phosphorylation without adrenergic stimulation, thus facilitating the evolution of exceptionally high resting heart rates (>1100 beats/minute). Cardiac transcriptomes further reveal alternative splicing ofTNNI3exon 3 in two distantly related bat families, thereby representing an intermediate state preceding the genomic assimilation of exon 3 skipping. As humanTNNI3may similarly be amenable to exon 3 alternative splicing, our results offer a new approach to restore diastolic function in chronic heart failure patients.One-Sentence SummaryShrews and moles independently evolved a truncated cardiac troponin I to facilitate rapid heart rates without chronic adrenergic stimulation.

LIMK1 and LIMK2 is enriched within the tumor in NT animals but diminished in LIMK1/2 KD tumors.

The aggressive brain tumor glioblastoma (GBM) is characterized by rapid cellular infiltration of brain tissue, raising the possibility that disease progression could potentially be slowed by disrupting the machinery of cell migration. The LIM kinase isoforms LIMK1 and LIMK2 (LIMK1/2) play important roles in cell polarization, migration, and invasion and are markedly upregulated in GBM and many other infiltrative cancers. Yet, it remains unclear whether LIMK suppression could serve as a viable basis for combating GBM infiltration. In this study, we investigated effects of LIMK1/2 suppression on GBM invasion by combining GBM culture models, engineered invasion paradigms, and mouse xenograft models. While knockdown of either LIMK1 or LIMK2 only minimally influenced invasion in culture, simultaneous knockdown of both isoforms strongly reduced the invasive motility of continuous culture models and human GBM tumor-initiating cells (TIC) in both Boyden chamber and 3D hyaluronic acid spheroid invasion assays. Furthermore, LIMK1/2 functionally regulated cell invasiveness, in part, by disrupting polarized cell motility under confinement and cell chemotaxis. In an orthotopic xenograft model, TICs stably transduced with LIMK1/2 shRNA were implanted intracranially in immunocompromised mice. Tumors derived from LIMK1/2 knockdown TICs were substantially smaller and showed delayed growth kinetics and more distinct margins than tumors derived from control TICs. Overall, LIMK1/2 suppression increased mean survival time by 30%. These findings indicate that LIMK1/2 strongly regulate GBM invasive motility and tumor progression and support further exploration of LIMK1/2 as druggable targets.Significance:Targeting the actin-binding proteins LIMK1 and LIMK2 significantly diminishes glioblastoma invasion and spread, suggesting the potential value of these proteins as therapeutic targets.

Supplemental Video 1. LIMK1/2 KD U373s exhibit abnormal actin turnover

Sequences of shRNAs expressed by LIMK1/2 knockdown cells.

The maize ligule is a fringe of epidermis-derived tissue, which arises from the preligule band (PLB) at a boundary between the blade and sheath. A hinge-like auricle also develops immediately distal to the ligule and contributes to blade angle. Here, we characterize the stages of PLB and early ligule development in terms of topography, cell area, division orientation, cell wall rigidity, and auxin response dynamics. Differential thickening of epidermal cells and localized periclinal divisions contributed to the formation of a ridge within the PLB, which ultimately produces the ligule fringe. Patterns in cell wall rigidity were consistent with the subdivision of the PLB into two regions along a distinct line positioned at the nascent ridge. The proximal region produces the ligule, while the distal region contributes to one epidermal face of the auricles. Whereas the auxin transporter PIN1 accumulated in the PLB, observed differential auxin transcriptional response did not underlie the partitioning of the PLB. Our data demonstrate that two zones with contrasting cellular properties, the preligule and preauricle, are specified within the ligular region prior to ligule outgrowth.Summary StatementChanges in cell geometry, division orientation, and cell wall mechanics underlie maize ligule morphogenesis. The establishment of mechanically distinct epidermal domains coincides with topographical changes during early ligule outgrowth.

This research work focusses on the implementation of a viscoplastic creep model in the thermomechanical simulation of the wire arc additive manufacturing (WAAM) process for Ti-6Al-4 V structures. Due to the characteristic layer by layer manufacturing within the WAAM process, viscoplastic material effects occur, which can be covered by implementing a creep model in the thermomechanical simulation. Experimental creep tests with a wide temperature, load and time range were carried out to examine short-term creep behaviour in particular. A Norton-Bailey creep law is used to accurately fit the experimental data and describe the base material’s creep behaviour. Subsequently, the fitted Norton-Bailey creep law was implemented in the thermomechanical simulation of the WAAM process. Finally, to determine the effect of creep on global distortion and local residual stress state in the substrate, simulations of a simplified linear, three-layer WAAM structure, with and without applying the implemented creep law, were carried out and compared to experimental data. The thermomechanical simulation with implemented creep model reveals a significant improvement in the numerical estimation of distortion and residual stress state in the substrate. The maximum distortion is reduced by about 13% and respectively the mean absolute percentage error between simulation and experiment decreases by about 34%. Additionally, the estimation accuracy with respect to the local residual stress state in the substrate improved by about 10%.

The study of regressive evolution has yielded a wealth of examples where the underlying genes bear molecular signatures of trait degradation, such as pseudogenization or deletion. Typically, it appears that such disrupted genes are limited to the function of the regressed trait, whereas pleiotropic genes tend to be maintained by natural selection to support their myriad purposes. One such set of pleiotropic genes is involved in the synthesis (We examinedWe report that crocodylians retain intact melatonin genes and expressThe losses of melatonin synthesis and signaling date to tens of millions of years ago in several lineages of placental mammals, raising questions about the evolutionary resilience of pleiotropic genes, and the causes and consequences of losing melatonin pathways in these species.

Evidence mounts that the steady-state cellular water efflux (unidirectional) first-order rate constant (k

Die UN-Behindertenrechtskonvention und das Bundesteilhabegesetz stellen den Begriff der Partizipation/Teilhabe in den Mittelpunkt. Ziel aller Masnahmen ist, das „Eingebundensein in Lebenssituationen“ der Kinder zu verbessern. Diese Zielorientierung gilt fur die Kinder- und Jugendrehabilitation und die sozialpadiatrische Versorgung ebenso wie ein inklusives Bildungssystem und die Jugendhilfe. Der Begriff der Partizipation/Teilhabe wird umrissen, und der konzeptuelle Hintergrund sowie wesentliche Aspekte wie Familienorientierung und teilhabeorientierte Prozesse werden geklart. Literaturrecherche, Daten aus den Statistiken der Leistungstrager sowie aktuelle qualitative empirische Daten werden prasentiert. Der Paradigmenwechsel von funktionsverbessernden zu teilhabe- und familienorientierten Angeboten erfolgt zunehmend, die Umsetzung wird allerdings durch die zogerliche Anpassung im Sozialrecht und den notwendigen komplexen Umbau der stark gegliederten Versorgung von Kindern und Jugendlichen mit und ohne chronische Gesundheitsstorungen und Behinderungen erschwert. Es mussen auf vielen Ebenen der Sozialgesetzgebung, der Kooperation der Trager, der Leistungserbringer, im Bildungswesen und in der Kinder- und Jugendhilfe noch grose Anstrengungen unternommen werden, die historisch gewachsene Segregation entlang von Behinderungsarten und Settings zu uberwinden.

We introduce a new

Elephants and sea cows and tenrecs; hyraxes and aardvarks and sengis and golden moles. What do these very divergent and different looking mammals have in common? They are each other's closest living relatives, and all belong to the placental mammal clade Afrotheria ('African beasts'), which is one of the four major clades of placental mammals along with Xenarthra (anteaters, sloths, armadillos), Euarchontoglires (e.g. rodents, rabbits, primates), and Laurasiatheria (e.g. bats, carnivorans, odd-toed and even-toed ungulates) (Figure 1). Unlike many animal groups that were recognized and named long ago based on anatomical features, the Afrotheria emerged as a natural clade only in the 1990s when molecular techniques were applied to the problem of placental mammal classification. The recognition of Afrotheria represents a triumph of molecular phylogenetics and brings together a fantastically diverse assemblage of placental mammals with widely disparate ecological and morphological adaptations. Although Afrotheria was not previously proposed based on studies of anatomical characters, additional support for the monophyly of this clade comes from geography and the fossil record. Specifically, the six extant orders in Afrotheria share with each other early fossil representatives that are known from Africa or along the margins of the ancient Tethys Sea, hence Afrotheria.

Summary coalescent methods offer an alternative to the concatenation (supermatrix) approach for inferring phylogenetic relationships from genome-scale datasets. Given huge datasets, broad congruence between contrasting phylogenomic paradigms is often obtained, but empirical studies commonly show some well supported conflicts between concatenation and coalescence results and also between species trees estimated from alternative coalescent methods. Partitioned support indices can help arbitrate these discrepancies by pinpointing outlier loci that are unjustifiably influential at conflicting nodes. Partitioned coalescence support (PCS) recently was developed for summary coalescent methods, such as ASTRAL and MP-EST, that use the summed fits of individual gene trees to estimate the species tree. However, PCS cannot be implemented when distance-based coalescent methods (e.g., STAR, NJst, ASTRID, STEAC) are applied. Here, this deficiency is addressed by automating computation of ‘partitioned coalescent branch length’ (PCBL), a novel index that uses iterative removal of individual gene trees to assess the impact of each gene on every clade in a distance-based coalescent tree. Reanalyses of five phylogenomic datasets show that PCBL for STAR and NJst trees helps quantify the overall stability/instability of clades and clarifies disagreements with results from optimality-based coalescent analyses. PCBL scores reveal severe ‘missing taxa’, ‘apical nesting’, ‘misrooting’, and ‘basal dragdown’ biases. Contrived examples demonstrate the gross overweighting of outlier gene trees that drives these biases. Because of interrelated biases revealed by PCBL scores, caution should be exercised when using STAR and NJst, in particular when many taxa are analyzed, missing data are non-randomly distributed, and widespread gene-tree reconstruction error is suspected. Similar biases in the optimality-based coalescent method MP-EST indicate that congruence among species trees estimated via STAR, NJst, and MP-EST should not be interpreted as independent corroboration for phylogenetic relationships. Such agreements among methods instead might be due to the common defects of all three summary coalescent methods.

BACKGROUND The shutter-speed model dynamic contrast-enhanced (SSM-DCE) MRI pharmacokinetic analysis adds a metabolic dimension to DCE-MRI. This is of particular interest in cancers, since abnormal metabolic activity might happen. PURPOSE To develop a DCE-MRI SSM analysis framework for glioblastoma multiforme (GBM) cases considering the heterogeneous tissue found in GBM. STUDY TYPE Prospective. SUBJECTS Ten GBM patients. FIELD STRENGTH/SEQUENCE 3T MRI with DCE-MRI. ASSESSMENTS The corrected Akaike information criterion (AICc ) was used to automatically separate DCE-MRI data into proper SSM versions based on the contrast agent (CA) extravasation in each pixel. The supra-intensive parameters, including the vascular water efflux rate constant (kbo ), the cellular efflux rate constant (kio ), and the CA vascular efflux rate constant (kpe ), together with intravascular and extravascular-extracellular water mole fractions (pb and po , respectively) were determined. Further error analyses were also performed to eliminate unreliable estimations on kio and kbo . STATISTICAL TESTS Student's t-test. RESULTS For tumor pixels of all subjects, 88% show lower AICc with SSM than with the Tofts model. Compared to normal-appearing white matter (NAWM), tumor tissue showed significantly larger pb (0.045 vs. 0.011, P

G.M.H. was funded by a UCD Ad Astra Fellowship. C.L. was funded by a UCD Ad Astra studentship. L.R. was funded by an SFI Centre for Research Training in Genomics Data Science grant (18/CRT/6214). L.M.D. was supported in part by NSF awards 1838273 and 2032063. E.C.T. and T.L. were funded by an SFI Frontiers for the Future Programme grant (19/FFP/6790). Relationships among laurasiatherian clades represent one of the most highly disputed topics in mammalian phylogeny. In this study, we attempt to disentangle laurasiatherian interordinal relationships using two independent genome-level approaches: (1) quantifying retrotransposon presence/absence patterns, and (2) comparisons of exon datasets at the levels of nucleotides and amino acids. The two approaches revealed contradictory phylogenetic signals, possibly due to a high level of ancestral incomplete lineage sorting. The positions of Eulipotyphla and Chiroptera as the first and second earliest divergences were consistent across the approaches. However, the phylogenetic relationships of Perissodactyla, Cetartiodactyla, and Ferae, were contradictory. While retrotransposon insertion analyses suggest a clade with Cetartiodactyla and Ferae, the exon dataset favoured Cetartiodactyla and Perissodactyla. Future analyses of hitherto unsampled laurasiatherian lineages and synergistic analyses of retrotransposon insertions, exon and conserved intron/intergenic sequences might unravel the conflicting patterns of relationships in this major mammalian clade. Publisher PDF

The loss of teeth and evolution of baleen racks in Mysticeti was a profound transformation that permitted baleen whales to radiate and diversify into a previously underutilized ecological niche of bulk filter-feeding on zooplankton and other small prey. Ancestral state reconstructions suggest that teeth were lost in the common ancestor of crown Mysticeti. Genomic studies provide some support for this hypothesis and suggest that the genetic toolkit for enamel production was inactivated in the common ancestor of living baleen whales. However, molecular studies to date have not provided direct evidence for the complete loss of teeth, including their dentin component, on the stem mysticete branch. Given these results, several questions remain unanswered: (1) Were teeth lost in a single step or did enamel loss precede dentin loss? (2) Was enamel lost early or late on the stem mysticete branch? (3) If enamel and dentin/tooth loss were decoupled in the ancestry of baleen whales, did dentin loss occur on the stem mysticete branch or independently in different crown mysticete lineages? To address these outstanding questions, we compiled and analyzed complete protein-coding sequences for nine tooth-related genes from cetaceans with available genome data. Seven of these genes are associated with enamel formation (ACP4, AMBN, AMELX, AMTN, ENAM, KLK4, MMP20) whereas two other genes are either dentin-specific (DSPP) or tooth-specific (ODAPH) but not enamel-specific. Molecular evolutionary analyses indicate that all seven enamel-specific genes have inactivating mutations that are scattered across branches of the mysticete tree. Three of the enamel genes (ACP4, KLK4, MMP20) have inactivating mutations that are shared by all mysticetes. The two genes that are dentin-specific (DSPP) or tooth-specific (ODAPH) do not have any inactivating mutations that are shared by all mysticetes, but there are shared mutations in Balaenidae as well as in Plicogulae (Neobalaenidae + Balaenopteroidea). These shared mutations suggest that teeth were lost at most two times. Shared inactivating mutations and dN/dS analyses, in combination with cetacean divergence times, were used to estimate inactivation times of genes and by proxy enamel and tooth phenotypes. The results of these analyses are most compatible with a two-step model for the loss of teeth in the ancestry of living baleen whales: enamel was lost very early on the stem Mysticeti branch followed by the independent loss of dentin (and teeth) in the common ancestors of Balaenidae and Plicogulae, respectively. These results imply that some stem mysticetes, and even early crown mysticetes, may have had vestigial teeth comprised of dentin with no enamel. Our results also demonstrate that all odontocete species (in our study) with absent or degenerative enamel have inactivating mutations in one or more of their enamel genes.

This work was supported by ONR grants N000141613017 to E.L.C. and N.A. and N00014-18-1-2808 to C.S.B.; funds from the NMNH Rebecca G. Mead and James G. Mead Marine Mammal Endowment, NSF (USA) grant no. DEB-1457735 to M.S.S., P.A.M. and J.G.; Brothers Hartmann Foundation grant no. AB28148 to M.T.O.; NMFS, BOEM, and USA Navy funding to D.Ch. under the Atlantic Marine Assessment Program for Protected Species. M.L.M. was funded under the Marie Skłodowska-Curie grant agreement no 801199; E.L.C. by a Rutherford Discovery Fellowship from the Royal Society of New Zealand Te Apārangi. Irish Whale and Dolphin Group Cetacean Stranding scheme is part-funded by the National Parks and Wildlife Service. The deep sea has been described as the last major ecological frontier, as much of its biodiversity is yet to be discovered and described. Beaked whales (ziphiids) are among the most visible inhabitants of the deep sea, due to their large size and worldwide distribution, and their taxonomic diversity and much about their natural history remain poorly understood. We combine genomic and morphometric analyses to reveal a new Southern Hemisphere ziphiid species, Ramari's beaked whale, Mesoplodon eueu, whose name is linked to the Indigenous peoples of the lands from which the species holotype and paratypes were recovered. Mitogenome and ddRAD-derived phylogenies demonstrate reciprocally monophyletic divergence between M. eueu and True's beaked whale (M. mirus) from the North Atlantic, with which it was previously subsumed. Morphometric analyses of skulls also distinguish the two species. A time-calibrated mitogenome phylogeny and analysis of two nuclear genomes indicate divergence began circa 2 million years ago (Ma), with geneflow ceasing 0.35–0.55 Ma. This is an example of how deep sea biodiversity can be unravelled through increasing international collaboration and genome sequencing of archival specimens. Our consultation and involvement with Indigenous peoples offers a model for broadening the cultural scope of the scientific naming process. Publisher PDF

Metabolic deficits at brain–fluid barriers are an increasingly recognized feature of cognitive decline in older adults. At the blood–cerebrospinal fluid barrier, water is transported across the choroid plexus (CP) epithelium against large osmotic gradients via processes tightly coupled to activity of the sodium/potassium pump. Here, we quantify CP homeostatic water exchange using dynamic contrast-enhanced MRI and investigate the association of the water efflux rate constant (k(co)) with cognitive dysfunction in older individuals. Temporal changes in the longitudinal relaxation rate constant (R(1)) after contrast agent bolus injection were measured in a CP region of interest in 11 participants with mild cognitive dysfunction [CI; 73 ± 6 years] and 28 healthy controls [CN; 72 ± 7 years]. k(co) was determined from a modified two-site pharmacokinetic exchange analysis of the R(1) time-course. K(trans), a measure of contrast agent extravasation to the interstitial space was also determined. Cognitive function was assessed by neuropsychological test performance. k(co) averages 5.8 ± 2.7 s(−1) in CN individuals and is reduced by 2.4 s(−1) [ca. 40%] in CI subjects. Significant associations of k(co) with global cognition and multiple cognitive domains are observed. K(trans) averages 0.13 ± 0.07 min(−1) and declines with age [–0.006 ± 0.002 min(−1) yr(−1)], but shows no difference between CI and CN individuals or association with cognitive performance. Our findings suggest that the CP water efflux rate constant is associated with cognitive dysfunction and shows an age-related decline in later life, consistent with the metabolic disturbances that characterize brain aging.

Background: The study of regressive evolution has yielded a wealth of examples where the underlying genes bear molecular signatures of trait degradation, such as pseudogenization or deletion. Typically, it appears that such disrupted genes are limited to the function of the regressed trait, whereas pleiotropic genes tend to be maintained by natural selection to support their myriad purposes. One such set of pleiotropic genes is involved in the synthesis (AANAT, ASMT) and signaling (MTNR1A, MTNR1B) of melatonin, a hormone secreted by the vertebrate pineal gland. Melatonin provides a signal of environmental darkness, thereby influencing the circadian and circannual rhythmicity of numerous physiological traits. Therefore, the complete loss of a pineal gland and the underlying melatonin pathway genes seems likely to be maladaptive, unless compensated by extrapineal sources of melatonin. Methods: We examined AANAT, ASMT, MTNR1A and MTNR1B in 123 vertebrate species, including pineal-less placental mammals and crocodylians. We searched for inactivating mutations and modelled selective pressures (dN/dS) to test whether the genes remain functionally intact. Results: We report that crocodylians retain intact melatonin genes and express AANAT and ASMT in their eyes, whereas all four genes have been repeatedly inactivated in the pineal-less xenarthrans, pangolins, sirenians, and whales. Furthermore, colugos have lost these genes, and several lineages of subterranean mammals have partial melatonin pathway dysfunction. These results are supported by the presence of shared inactivating mutations across clades and analyses of selection pressure based on the ratio of non-synonymous to synonymous substitutions (dN/dS), suggesting extended periods of relaxed selection on these genes. Conclusions: The losses of melatonin synthesis and signaling date to tens of millions of years ago in several lineages of placental mammals, raising questions about the evolutionary resilience of pleiotropic genes, and the causes and consequences of losing melatonin pathways in these species.