Modal dependent type theory and dependent right adjoints

In recent years we have seen several new models of dependent type theory extended with some form of modal necessity operator, including nominal type theory, guarded and clocked type theory, and spatial and cohesive type theory. In this paper we study modal dependent type theory: dependent type theory with an operator satisfying (a dependent version of) the K-axiom of modal logic. We investigate both semantics and syntax. For the semantics, we introduce categories with families with a dependent right adjoint (CwDRA) and show that the examples above can be presented as such. Indeed, we show that any finite limit category with an adjunction of endofunctors gives rise to a CwDRA via the local universe construction. For the syntax, we introduce a dependently typed extension of Fitch-style modal lambda-calculus, show that it can be interpreted in any CwDRA, and build a term model. We extend the syntax and semantics with universes

Mammalian target of rapamycin inhibition impacts energy homeostasis and induces sex-specific body weight loss in humans

BACKGROUND: Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal-dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia. METHODS: Within a sub-analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex-specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis. RESULTS: Within the 2-year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P < 0.01). After 9 months, women and men had lost 2.6 ± 3.8 and 0.8 ± 1.5 kg (P < 0.05) in body weight, respectively, and after 21 months, they had lost 4.1 ± 6.6 and 1.0 ± 3.3 kg (P < 0.05), respectively. On everolimus, caloric intake was significantly lower in women versus men (1510 ± 128 vs. 2264 ± 216 kcal/day, P < 0.05), caused mainly by a lower fat and protein intake in women versus men. Cognitive restraints, disinhibition and hunger remained unchanged. In a subgroup of patients resting metabolic rate was unchanged whereas OGL-induced thermogenesis was reduced (7 ± 2 vs. 11 ± 2 kcal, P < 0.05). Fasting and OGL-induced fat oxidation was increased (P < 0.05) on versus off everolimus. In adipose tissue, fasting lipolytic activity was increased, but lipolytic activity was inhibited similarly after the OGL on versus off everolimus, respectively. In skeletal muscle, postprandial glucose uptake and aerobic glycolysis was reduced in patients on everolimus. CONCLUSIONS: mTOR inhibition by everolimus induces body weight reduction, specifically in female patients. This effect is possibly caused by a centrally mediated reduced food (fat and protein) intake and by centrally/peripherally mediated increased fat oxidation (systemic) and mobilization (adipose tissue). Glucose uptake and oxidation might be reduced in skeletal muscle. This could lead to cachexia and, possibly, muscle wasting. Therefore, our results have important implications for patients recieving immune-suppressive mTOR inhibition therapy

QuantiMus: A Machine Learning-Based Approach for High Precision Analysis of Skeletal Muscle Morphology.

Skeletal muscle injury provokes a regenerative response, characterized by the de novo generation of myofibers that are distinguished by central nucleation and re-expression of developmentally restricted genes. In addition to these characteristics, myofiber cross-sectional area (CSA) is widely used to evaluate muscle hypertrophic and regenerative responses. Here, we introduce QuantiMus, a free software program that uses machine learning algorithms to quantify muscle morphology and molecular features with high precision and quick processing-time. The ability of QuantiMus to define and measure myofibers was compared to manual measurement or other automated software programs. QuantiMus rapidly and accurately defined total myofibers and measured CSA with comparable performance but quantified the CSA of centrally-nucleated fibers (CNFs) with greater precision compared to other software. It additionally quantified the fluorescence intensity of individual myofibers of human and mouse muscle, which was used to assess the distribution of myofiber type, based on the myosin heavy chain isoform that was expressed. Furthermore, analysis of entire quadriceps cross-sections of healthy and mdx mice showed that dystrophic muscle had an increased frequency of Evans blue dye+ injured myofibers. QuantiMus also revealed that the proportion of centrally nucleated, regenerating myofibers that express embryonic myosin heavy chain (eMyHC) or neural cell adhesion molecule (NCAM) were increased in dystrophic mice. Our findings reveal that QuantiMus has several advantages over existing software. The unique self-learning capacity of the machine learning algorithms provides superior accuracy and the ability to rapidly interrogate the complete muscle section. These qualities increase rigor and reproducibility by avoiding methods that rely on the sampling of representative areas of a section. This is of particular importance for the analysis of dystrophic muscle given the "patchy" distribution of muscle pathology. QuantiMus is an open source tool, allowing customization to meet investigator-specific needs and provides novel analytical approaches for quantifying muscle morphology

Transient receptor potential vanilloid 4 channel deficiency aggravates tubular damage after acute renal ischaemia reperfusion

Transient receptor potential vanilloid 4 (TRPV4) cation channels are functional in all renal vascular segments and mediate endothelium-dependent vasorelaxation. Moreover, they are expressed in distinct parts of the tubular system and activated by cell swelling. Ischaemia/reperfusion injury (IRI) is characterized by tubular injury and endothelial dysfunction. Therefore, we hypothesised a putative organ protective role of TRPV4 in acute renal IRI. IRI was induced in TRPV4 deficient (Trpv4 KO) and wild-type (WT) control mice by clipping the left renal pedicle after right-sided nephrectomy. Serum creatinine level was higher in Trpv4 KO mice 6 and 24 hours after ischaemia compared to WT mice. Detailed histological analysis revealed that IRI caused aggravated renal tubular damage in Trpv4 KO mice, especially in the renal cortex. Immunohistological and functional assessment confirmed TRPV4 expression in proximal tubular cells. Furthermore, the tubular damage could be attributed to enhanced necrosis rather than apoptosis. Surprisingly, the percentage of infiltrating granulocytes and macrophages were comparable in IRI-damaged kidneys of Trpv4 KO and WT mice. The present results suggest a renoprotective role of TRPV4 during acute renal IRI. Further studies using cell-specific TRPV4 deficient mice are needed to clarify cellular mechanisms of TRPV4 in IRI

Dental Anxiety and Fear among Patients in Jazan, Kingdom of Saudi Arabia: A Cross-sectional Study

n/

QuantiMus: A Machine Learning-Based Approach for High Precision Analysis of Skeletal Muscle Morphology

Skeletal muscle injury provokes a regenerative response, characterized by the de novo generation of myofibers that are distinguished by central nucleation and re-expression of developmentally restricted genes. In addition to these characteristics, myofiber crosssectional area (CSA) is widely used to evaluate muscle hypertrophic and regenerative responses. Here, we introduce QuantiMus, a free software program that uses machine learning algorithms to quantify muscle morphology and molecular features with high precision and quick processing-time. The ability of QuantiMus to define and measure myofibers was compared to manual measurement or other automated software programs. QuantiMus rapidly and accurately defined total myofibers and measured CSA with comparable performance but quantified the CSA of centrally-nucleated fibers (CNFs) with greater precision compared to other software. It additionally quantified the fluorescence intensity of individual myofibers of human and mouse muscle, which was used to assess the distribution of myofiber type, based on the myosin heavy chain isoform that was expressed. Furthermore, analysis of entire quadriceps cross-sections of healthy and mdx mice showed that dystrophic muscle had an increased frequency of Evans blue dye+ injured myofibers. QuantiMus also revealed that the proportion of centrally nucleated, regenerating myofibers that express embryonic myosin heavy chain (eMyHC) or neural cell adhesion molecule (NCAM) were increased in dystrophic mice. Our findings reveal that QuantiMus has several advantages over existing software. The unique self-learning capacity of the machine learning algorithms provides superior accuracy and the ability to rapidly interrogate the complete muscle section. These qualities increase rigor and reproducibility by avoiding methods that rely on the sampling of representative areas of a section. This is of particular importance for the analysis of dystrophic muscle given the “patchy” distribution of muscle pathology. QuantiMus is an open source tool, allowing customization to meet investigatorspecific needs and provides novel analytical approaches for quantifying muscle morphology

Evaluation of the shear bond strength of a tricalcium silicate-based material to four self-adhering glass ionomer materials: an in vitro study

BackgroundThis study aimed to evaluate and compare the shear bond strength (SBS) of EQUIA Forte HT with that of other restorative materials, including EQUIA Forte, glass ionomer cement (GIC), and resin-modified glass ionomer cement (RMGIC) when bonded to NeoMTA 2.Materials and methodsA total of 120 holes were created in Teflon molds and filled with NeoMTA 2. The restorative materials were immediately applied using customized silicone molds. The samples were randomly divided into two main groups: one to measure the immediate SBS and the other to measure the delayed SBS. These two main groups were further divided into four subgroups based on the restorative material used: EQUIA Forte HT, EQUIA Forte, GIC, and RMGIC.ResultsThe study groups showed statistically significant differences in the mean SBS (p &lt; 0.0001). The immediate SBS of the RMGIC group (mean ± SD: 5.43 ± 1.22) was significantly higher than those of the GIC and EQUIA Forte groups, with no significant difference found compared to the SBS of EQUIA Forte HT. In the delayed SBS, both the RMGIC and EQUIA Forte HT groups (4.98 ± 0.67 and 4.93 ± 0.60, respectively) demonstrated significantly higher bond strengths than the GIC and EQUIA Forte groups (3.81 ± 0.57 and 4.2 ± 0.63, respectively). However, there were no statistically significant differences between the RMGIC and EQUIA Forte HT groups or between the GIC and EQUIA Forte groups.ConclusionBased on our findings, EQUIA Forte HT has shown promising outcomes when used as a restorative material following pulpotomies, with results comparable to those of RMGIC

Influence of spark ignition in the determination of Markstein lengths using spherically expanding flames

Constant pressure outwardly propagating flame experiments in a spherical bomb are performed to examine the duration and radius over which spark ignition effects persist. This is motivated by the need to properly account for such effects in the measurement of laminar burning velocity and Markstein length using the spark ignited expanding flame technique. Ignition energy was varied and its effects on flame propagation in methane-air and isooctane-air mixtures were studied. The Markstein length of the mixture proved critical in the ignition energy dependency of flame propagation. For relatively high values, an underlying common variation of self-sustaining flame speed with radius can be identified by the rapid convergence of curves for different ignition energies. As the Markstein length decreases, low energy spark ignition is found to give rise to a distorted and wrinkled flame kernel. For such mixtures, due to the weak effect of stretch, the kernel subsequently develops into a non-spherically propagating flame. In these cases the spark ignition effect persists up to large radius. It is shown that using low ignition energy leads to a flame speed, during the development phase, which is higher than that of a self-sustaining spherical flame. It is further shown that if this effect is not accounted for, measurements of Markstein length using standard fitting techniques results in a large error. This problem is found to worsen as the Markstein length decreases, such that its apparent measured value becomes increasingly influenced by any distortions of the flame kernel produced by the spark

Proteome changes in autosomal recessive primary microcephaly

Background/aim: : Autosomal recessive primary microcephaly (MCPH) is a rare and genetically heterogeneous group of disorders characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. MCPH3 is caused by biallelic variants in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the corresponding Cdk5rap2 mutant or Hertwig's anemia mouse model, congenital microcephaly as well as defects in the hematopoietic system, germ cells and eyes have been reported. The reduction in brain volume, particularly affecting gray matter, has been attributed mainly to disturbances in the proliferation and survival of early neuronal progenitors. In addition, defects in dendritic development and synaptogenesis exist that affect the excitation-inhibition balance. Here, we studied proteomic changes in cerebral cortices of Cdk5rap2 mutant mice. Material and methods: : We used large-gel two-dimensional gel (2-DE) electrophoresis to separate cortical proteins. 2-DE gels were visualized by a trained observer on a light box. Spot changes were considered with respect to presence/absence, quantitative variation and altered mobility. Result: : We identified a reduction in more than 30 proteins that play a role in processes such as cell cytoskeleton dynamics, cell cycle progression, ciliary functions and apoptosis. These proteome changes in the MCPH3 model can be associated with various functional and morphological alterations of the developing brain. Conclusion: : Our results shed light on potential protein candidates for the disease-associated phenotype reported in MCPH3

Linear programs and convex hulls over fields of puiseux fractions

We describe the implementation of a subfield of the field of formal Puiseux series in polymake. This is employed for solving linear programs and computing convex hulls depending on a real parameter. Moreover, this approach is also useful for computations in tropical geometry