Effects of Cognitive Load on Vocal Fold Vibratory Patterns in Bilingual Speakers of Low and High German.

OBJECTIVES: Increased cognitive load has been observed to correlate with decreased vocal fold perturbation, reduced additive noise, increased periodicity, and a higher rate of vocal fold vibration. The aim of this study was to explore whether vocal fold vibratory patterns can serve as indicators of increased cognitive load in nonbalanced bilingual speakers when they use their weaker language. STUDY DESIGN: This is a comparative experimental study with a within-speaker design. METHODS: We recorded a total of 95 bilingual speakers of Low German (LG), which is an endangered language spoken in Northern Germany, and Standard High German (HG). Participants completed four tasks in both languages: engaging in free narration, describing a picture story, giving directions, and reading a narrative passage. For the last three tasks, the difficulty levels were varied. Measurements included jitter, shimmer, harmonics-to-noise ratio (HNR), cepstral peak prominence (CPP), the proportion of creak, pitch level, and pitch span. Changes in voice characteristics were examined both in terms of the participants' age and their language dominance. For the latter, we calculated a dominance score derived from age of acquisition, frequency of use, and self-perceived linguistic competence in the two languages. RESULTS: Younger speakers showed a higher dominance of HG over LG, which decreased with age. Younger and more HG-dominant speakers exhibited lower jitter and shimmer, along with a higher HNR and a lower creak proportion in LG compared to HG. CPP and pitch level were higher in LG but showed little variation with age or language dominance. No clear effects on pitch span were observed. Overall, age was a slightly more reliable predictor than language dominance. Acoustic differences in voice quality were about equally detectable across the different speech tasks while varying difficulty levels had minimal impact. CONCLUSIONS: The variation in vocal fold vibratory patterns suggests that younger and more HG-dominant speakers experienced greater cognitive load when speaking LG. Given that increased cognitive load may negatively impact language usage, voice analysis opens up new possibilities for evaluating the future prospects of endangered languages.

L1 variation and L2 acquisition: L1 German /eː/-/ɛː/ overlap and its effect on the acquisition of L2 English /ɛ/-/æ/.

A person's first language (L1) affects the way they acquire speech in a second language (L2). However, we know relatively little about the role different varieties of the L1 play in the acquisition of L2 speech. This study focuses on German (L1) learners of English (L2) and asks whether the degree to which German speakers distinguish between the two vowels /eː/ and /ɛː/ in their L1 has an impact on how well these individuals identify /æ/ and discriminate between the two English vowels /ɛ/ and /æ/. These two English vowels differ in both vowel quality and duration (/æ/ is longer than /ɛ/). We report on an identification and a discrimination experiment. In the first study, participants heard a sound file and were asked to indicate whether they heard "pen" or "pan" (or "pedal" or "paddle"). The stimuli differed from each other in terms of both vowel quality (11 steps on a spectral continuum from an extreme /æ/ to an extreme /ɛ/) and duration (short, middle, long). In the second study, participants had to signal whether two sound files they were exposed to differed from each other. We modeled the percentage of /æ/ ("pan," "paddle") selection (identification task only, binomial logistic regression), accuracy (discrimination task only, binomial logistic regression), and reaction time (identification and discrimination tasks, linear mixed effects models) by implementing the German Pillai score as a measure of vowel overlap in our analysis. Each participant has an individual Pillai score, which ranges from 0 (= merger of L1 German /eː/ and /ɛː/) to 1 (=maintenance of the contrast between L1 German /eː/ and /ɛː/) and had been established, prior to the perception experiments reported here, in a production study. Although the findings from the discrimination study remain inconclusive, the results from the identification test support the hypothesis that maintaining the vowel contrast in the L1 German leads to a more native-like identification of /æ/ in L2 English. We conclude that sociolinguistic variation in someone's L1 can affect L2 acquisition.

Adding Safety Rules to Surgeon-Authored Virtual Reality Training.

INTRODUCTION: The Toolkit for Illustration of Procedures in Surgery (TIPS) is an open source virtual reality (VR) laparoscopic simulation-based training environment with force feedback. The TIPS-author is a content creation interface that allows a surgeon educator (SE) to assemble new laparoscopic training modules. New technology enables safety rules to be specified by the SE, automatically tracks specified safety errors, and summarizes and communicates achievements and errors to the surgical trainee. METHODS: The TIPS-author combines and initializes building blocks of anatomy with their physical properties, as selected by the SE from a database. The SE can add any safety rule that can be tested in terms of location, proximity, separation, clip count, and force. Errors are then automatically monitored during simulation and recorded as visual snapshots for feedback to the trainee. The TIPS was field tested at 2 surgical conferences, one before and one after adding the error snapshot feature. RESULTS: Sixty-four respondents at 2 surgical conferences assessed the utility of TIPS on a Likert scale. While other ratings remained unchanged for an overall score of 5.24 of 7 (7 = very useful), the rating of the statement "The TIPS interface helps learners understand the force necessary to explore the anatomy" improved from 5.04 to 5.35 of 7 after the snapshot mechanism was added. CONCLUSIONS: The ratings indicate the viability of the TIPS open source SE-authored surgical training units with safety rules. Presenting SE-determined procedural missteps via the snapshot mechanism at the end of the training increases perceived utility.

Plastic hexahedral FEM for surgical simulation.

PURPOSE: Soft-tissue manipulations, such as collecting, stretching or tearing tissue, are a common component of surgery. When too much force is applied, these manipulations result in a residual plastic deformation that surgeons should be aware of and that should be modeled by surgical simulation. METHODS: Many tissues, vessels and organs can be modeled as offsets of curved simple shapes with primary directions, e.g., radial and axial for cylinders yield a rectangular mesh whose normal offset naturally yields a hexahedral mesh that can serve as a thick shell. Other organs are easy to embed into and deform following a hex mesh. We extend existing code for the volumetric finite element method (FEM) to model tissue plasticity as hexahedral thick shells or embedded organs. Specifically, the work extends the open source Simulation Open Framework Architecture and its newest hyperelastic deformation addition, Caribou, with focus on surgical simulation. The extension factors deformation gradients into (corotational or hyperelastic) elastic factors and plastic factors and enforces volume preservation. Limits on per-element twist, twist torque, material hardening and bounds on plasticity where elements invert avoid the need for re-meshing. RESULTS: Our hexahedral FEM avoids the biased outcomes of asymmetric coarsely-partitioned tetrahedral FEM. Caribou's hyperelastic FEM is extended to hex-FEM stretching plasticity. Our high-order accurate blended-vertex deformation enables coarse hex meshes to model large plastic rotational and stretch deformations without re-meshing. We compare a vertex-blended to a cell-centered piecewise constant approach; contrast plasticity based on corotational FEM and hyperelastic FEM; and test the computation under mesh refinement. The volume is preserved also for large deformations. CONCLUSION: On-the-fly generated hexahedral meshes can directly be used as finite element domains for plastic deformation based on corotational or hyperelastic elasticity. The outcome is suitable for surgical simulation.

Overexpression of Renin-B Induces Warburg-like Effects That Are Associated with Increased AKT/mTOR Signaling.

The classical secretory renin-a is known to be involved in angiotensin generation, thereby regulating not only blood pressure, but also promoting oxidative stress as well as apoptotic and necrotic cell death. In contrast, another cytosolic renin isoform named renin-b has been described, exerting protective effects under ischemia-related conditions in H9c2 cardiomyoblasts. Using microarray-based transcriptome analyses, we aimed to identify the signaling pathways involved in mediating cardioprotection in H9c2 cells overexpressing renin-b. By transcriptome profiling, we identified increased gene expression of several genes encoding glycolytic enzymes and glucose transporters, while the transcript levels of TCA-cycle enzymes were decreased. Complementing data from metabolic analyses revealed enhanced glucose consumption and lactate accumulation due to renin-b overexpression. Renin-b overexpression further stimulated AKT/mTOR signaling, where numerous genes involved in this pathway showed altered transcript levels. For AKT, we also detected enhanced phosphorylation levels by means of Western blotting, suggesting an activation of this kinase. Moreover, analysis of the ROS levels identified an increase in ROS accumulation in renin-b-overexpressing cells. Altogether, our data demonstrate that renin-b overexpression induces the metabolic remodeling of H9c2 cells similar to that seen under oxygen deprivation. This metabolic phenotype exerting so-called aerobic glycolysis is also known as the Warburg effect.

Functions of the (pro)renin receptor (Atp6ap2) at molecular and system levels: pathological implications in hypertension, renal and brain development, inflammation, and fibrosis.

The (pro)renin receptor [(P)RR, Atp6ap2] was initially discovered as a membrane-bound binding partner of prorenin and renin. A soluble (P)RR has additional paracrine effects and is involved in metabolic syndrome and kidney damage. Meanwhile it is clear that most of the effects of the (P)RR are independent of prorenin. In the kidney, (P)RR plays an important role in renal dysfunction by activating proinflammatory and profibrotic molecules. In the brain, (P)RR is expressed in cardiovascular regulatory nuclei and is linked to hypertension. (P)RR is known to be an essential component of the v-ATPase as a key accessory protein and plays an important role in kidney, brain and heart via regulating the pH of the extracellular space and intracellular compartments. V-ATPase and (P)RR together act on WNT and mTOR signalling pathways, which are responsible for cellular homeostasis and autophagy. (P)RR through its role in v-ATPase assembly and function is also important for fast recycling endocytosis by megalin. In the kidney, megalin together with v-ATPase and (P)RR is crucial for endocytic uptake of components of the RAS and their intracellular processing. In the brain, (P)RR, v-ATPases and megalin are important regulators both during development and in the adult. All three proteins are associated with diseases such as XLMR, XMRE, X-linked parkinsonism and epilepsy, cognitive disorders with Parkinsonism, spasticity, intellectual disability, and Alzheimer's Disease which are characterized by impaired neuronal function and/or neuronal loss. The present review focusses on the relevant effects of Atp6ap2 without assigning them necessarily to the RAS. Mechanistically, many effects can be well explained by the role of Atp6ap2 for v-ATPase assembly and function. Furthermore, application of a soluble (P)RR analogue as new therapeutic option is discussed.

Overexpression of Transcripts Coding for Renin-b but Not for Renin-a Reduce Oxidative Stress and Increase Cardiomyoblast Survival under Starvation Conditions.

A stimulated renin-angiotensin system is known to promote oxidative stress, apoptosis, necrosis and fibrosis. Renin transcripts (renin-b; renin-c) encoding a cytosolic renin isoform have been discovered that may in contrast to the commonly known secretory renin (renin-a) exert protective effects Here, we analyzed the effect of renin-a and renin-b overexpression in H9c2 cardiomyoblasts on apoptosis and necrosis as well as on potential mechanisms involved in cell death processes. To mimic ischemic conditions, cells were exposed to glucose starvation, anoxia or combined oxygen-glucose deprivation (OGD) for 24 h. Under OGD, control cells exhibited markedly increased necrotic and apoptotic cell death accompanied by enhanced ROS accumulation, loss of mitochondrial membrane potential and decreased ATP levels. The effects of OGD on necrosis were exaggerated in renin-a cells, but markedly diminished in renin-b cells. However, with respect to apoptosis, the effects of OGD were almost completely abolished in renin-b cells but interestingly also moderately diminished in renin-a cells. Under glucose depletion we found opposing responses between renin-a and renin-b cells; while the rate of necrosis and apoptosis was aggravated in renin-a cells, it was attenuated in renin-b cells. Based on our results, strategies targeting the regulation of cytosolic renin-b as well as the identification of pathways involved in the protective effects of renin-b may be helpful to improve the treatment of ischemia-relevant diseases.

Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+ ).

Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel CaV3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1hM1560V/+ knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h-/- ). Adrenal morphology of both Cacna1hM1560V/+ and Cacna1h-/- mice was normal. Cacna1hM1560V/+ mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal Cyp11b2 (aldosterone synthase) expression was increased and remained elevated on a high-salt diet (relative autonomy, characteristic of primary aldosteronism), but plasma aldosterone was only elevated in male animals. The systolic blood pressure of Cacna1hM1560V/+ mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. Cacna1h-/- mice had elevated renal Ren1 (renin-1) expression but normal adrenal Cyp11b2 levels, suggesting that in the absence of CaV3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1hM1560V/+ adrenal slices showed increased baseline and peak intracellular calcium concentrations in the zona glomerulosa compared to controls, but the frequency of calcium spikes did not rise. We conclude that FH-IV, on a molecular level, is caused by elevated intracellular Ca2+ concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline Cacna1h gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of CaV3.2 channel function can be compensated for in a chronic setting.

Least Degree G 1-refinable Multi-sided Surfaces Suitable for Inclusion into C 1 bi-2 Splines.

Geometrically smooth spline surfaces, generalized to include n-sided facets or configurations of n ≠ 4 quads, can exhibit a curious lack of additional degrees of freedom for modelling or engineering analysis when refined. This paper establishes a minimal polynomial degree for smooth constructions of multi-sided surfaces that guarantees more flexibility in all directions under refinement. Degree bi-4 is both necessary and sufficient for flexibility-increasing G 1-refinability within a bi-quadratic C 1 spline complex. Sufficiency is proven by two alternative flexibly G 1-refinable constructions exhibiting good highlight line distributions.

Angiotensin dependent and angiotensin independent protective effects of renin-b in H9c2 cells after anoxia.

The renin-angiotensin system is known to regulate blood pressure as well as water- and electrolyte balance. An activated RAS is involved in the development of hypertension and hypertension-related organ damage. Thus, inhibitors of the RAS are protective and markedly increasing the life span of patients. In contrast, renin transcripts have been discovered encoding a cytoplasmatic renin isoform, termed renin-b, which is not harmful but may be even protective. Here we demonstrate that depletion of renin-b encoding transcripts by small interference RNA decreased ATP levels and increased basal necrosis as well as apoptosis rates. Furthermore, renin-b depletion potentiated the anoxia-induced increase of necrosis rates. Vice versa, overexpression of renin-b prevented the anoxia-induced increase of caspase-mediated apoptosis rates. Besides, cells overexpressing renin-b exhibited even reduced mitochondrial mediated apoptosis rates under anoxia, when compared with normoxic conditions, as indicated by Annexin V labeling. However, whereas the protective effect of renin-b on caspase-mediated apoptosis was completely blocked by the renin inhibitor CH732, the effect on mitochondrial-mediated apoptosis was not affected by CH732 at all. From these data we conclude that renin-b overexpression mediates cardioprotective effects under anoxia with respect to mitochondrial induced apoptosis angiotensin-independently, but with respect to caspase induced apoptosis likely in an angiotensin-dependent manner.

Low degree splines for locally quad-dominant meshes.

A mesh is locally quad-dominant (lqd) if all non-4-sided facets are surrounded by quadrilaterals. Lqd meshes allow for irregular nodes where n ≠ 4 quads meet and for multi-sided facets, called T-gons, that end quad-strips and so adjust mesh density. This paper introduces a new class of bi-cubic (bi-3) Geometric T-joint (GT) splines whose control nets are τ-nets, i.e. T-gons surrounded by quads. These GT-splines join smoothly with each other, bi-3 G-splines and regular C 1 bi-quadratic splines to form smooth surfaces of degree at most bi-3.

Smooth polar caps for locally quad-dominant meshes.

A polar configuration is a node surrounded by m triangles. Polar configurations are common to cap off cylinders and spheres. When the triangles, interpreted as quadrilaterals with one edge collapsed, are surrounded by a quad-strip then the extended polar configuration qualifies as part of a locally quad-dominant (lqd) mesh. Recent constructions, referred to as semi-structured splines, can use lqd meshes as control nets: multi-sided configurations that merge parameter directions are covered by G-spline; and T-junctions that transition from coarse and fine are covered by GT-splines. This paper complements existing semi-structured splines by providing the missing component for polar configurations. A spectrum of constructions of differing degree are introduced, tested and compared. Bi-2 C 1 splines are extended to polar configurations covered by C 1 surfaces consisting of (macro-)patches of degree as low as bi-2. Bi-3 C 2 splines are extended to polar configurations covered by surfaces that are C 2 except for a C 1 pole and consist of (macro-)patches of degree as low as bi-3.

Refinable tri-variate C 1 splines for box-complexes including irregular points and irregular edges.

C 1 splines over box-complexes generalize C 1 degree 3 (cubic) tensor-product splines. A box-complex is a collection of 3-dimensional boxes forming an unstructured hexahedral mesh that can include irregular points and irregular edges where the layout deviates from the tensor-product grid layout. For example, an edge shared and enclosed by five boxes is irregular. Where the mesh is locally regular, the restriction of the space to each box is a polynomial piece of the C 1 tri-cubic tensor-product spline, by default initialized as a C 2 tri-cubic. Boxes containing irregularities have their polynomials binarily split into 23 pieces to isolate the irregularity. The pieces join with matching derivatives. The derivatives are zero at irregularities, but these singularities are removable by a local change of variables. The space consists of 23 linearly independent functions per box and is refinable.

A sharp degree bound on G 2-refinable multi-sided surfaces.

Refinement of a space of splines should yield additional degrees of freedom for modeling and engineering analysis, both along boundaries and in the interior. Yet such additional flexibility fails to materialize for multi-sided G 2 surface constructions when the polynomial degree is too low. This paper establishes a tight lower bound on the polynomial degree of flexibility-increasing refinable multi-sided G 2 surface constructions within a C 2 spline complex - by ruling out bi-5 constructions and by exhibiting a multi-sided bi-6 construction that yields good highlight line and curvature distributions. The bi-6 construction consists of one 2 × 2 macro-patch for each of the n sectors that join to form the multi-sided surface.

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation.

Although the renin-angiotensin system usually promotes oxidative stress and cell death, renin transcripts have been discovered, whose transcription product may be cardioprotective. These transcripts encode a non-secretory renin isoform that is localized in the cytosol and within mitochondria. Here we tested the hypotheses that cytosolic renin [ren(2-9)] expression promotes cell survival under hypoxia and glucose depletion by preserving the mitochondrial membrane potential (∆Ψm) and mitigating the accumulation of ROS. To simulate ischemic insults, we exposed H9c2 cells to glucose deprivation, anoxia or to combined oxygen-glucose deprivation (OGD) for 24 hours and determined renin expression. Furthermore, H9c2 cells transfected with the empty pIRES vector (pIRES cells) or ren(2-9) cDNA-containing vector [ren(2-9) cells] were analyzed for cell death, ∆Ψm, ATP levels, accumulation of ROS, and cytosolic Ca2+ content. In pIRES cells, expression of ren(1A-9) was stimulated under all three ischemia-related conditions. After OGD, the cells lost their ∆Ψm and exhibited enhanced ROS accumulation, increased cytosolic Ca2+ levels, decreased ATP levels as well as increased cell death. In contrast, ren(2-9) cells were markedly protected from these effects. Ren(2-9) appears to represent a protective response to OGD by reducing ROS generation and preserving mitochondrial functions. Therefore, it is a promising new target for the prevention of ischemia-induced myocardial damage.

VR Simulation Leads to Enhanced Procedural Confidence for Surgical Trainees.

OBJECTIVE: Active learning techniques result in greater knowledge acquisition compared to passive methods. For medical students with limited hands-on operative experiences, virtual reality platforms represent active learning and may enhance procedural training. We hypothesize that virtual reality simulators like Toolkit for Illustration of Procedures in Surgery (TIPS) are a more effective modality in teaching laparoscopic surgical techniques to medical students when compared to passive learning tools like videos. DESIGN: In this crossover study, participants were randomly assigned to perform either a TIPS laparoscopic appendectomy followed by video of a laparoscopic cholecystectomy, or video of a laparoscopic appendectomy followed by TIPS laparoscopic cholecystectomy. A knowledge assessment followed each intervention. A postsurvey was used to gather feedback and subjective impressions of the learning experience. SETTING: University of Central Florida College of Medicine. PARTICIPANTS: Second, third, and fourth-year medical students (n = 37). RESULTS: Validation of the content assessments revealed strong internal consistency (Cronbach's α = 0.73). A 2-tailed Fisher's exact test revealed that the video had greater ease of use (p = 0.032), but TIPS had greater utility as a learning tool (p < 0.001) and instilled greater confidence in the ability to reproduce procedural steps (p < 0.001). A 2-tailed t test of the average content quiz scores revealed no significant difference in percentage correct between groups on the laparoscopic appendectomy quiz (p = 0.772), but a difference favoring video learning on the laparoscopic cholecystectomy quiz (p = 0.042) CONCLUSIONS: Video and TIPS both enhanced different aspects of student learning; however, the active TIPS platform produced greater confidence in the ability to reproduce the steps of the procedure and had greater utility as a learning strategy. Videos are simple to use and can serve a complementary role in curriculum design.

Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation.

Gain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II). Here, we report the generation of a mouse model carrying a missense mutation homologous to the most common FH-II-associated CLCN2 mutation. In these Clcn2R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2R180Q/+ mice have increased aldosterone:renin ratios as well as elevated blood pressure levels. The counterpart knockout model (Clcn2-/-), in contrast, requires elevated renin levels to maintain normal aldosterone levels. Adrenal slices of Clcn2R180Q/+ mice show increased calcium oscillatory activity. Together, our work provides a knockin mouse model with a mild form of primary aldosteronism, likely due to increased chloride efflux and depolarization. We demonstrate a role of ClC-2 in normal aldosterone production beyond the observed pathophysiology.

Fair free-form surfaces that are almost everywhere parametrically C 2.

Compared to G k continuity, C k continuity simplifies the construction of functions on surfaces and their refinement, e.g. to solve differential equations on the surface. The new class of almost everywhere parametrically C 2 free-form surfaces provide such a parameterization. For example, a new bi-6 construction combines a fast-contracting C 2 guided subdivision surface with a tiny multi-sided G 1 cap. The cap is chosen to be smaller than any refinement anticipated for geometric modeling or computing on surfaces. Fast contraction means that one subdivision step shrinks the remaining hole more than three steps of Catmull-Clark subdivision. This yields smooth surfaces consisting of a finite number of pieces that are suitable for engineering practice. Both the subdivision construction and the cap are guided by a reference surface. This guide conveys the basic shape, but has a different structure and lower smoothness.