Can changes in deformation regimes be inferred from crystallographic preferred orientations in polar ice?

Creep due to ice flow is generally thought to be the main cause for the formation of crystallographic preferred orientations (CPOs) in polycrystalline anisotropic ice. However, linking the development of CPOs to the ice flow history requires a proper understanding of the ice aggregate's microstructural response to flow transitions. In this contribution the influence of ice deformation history on the CPO development is investigated by means of full-field numerical simulations at the microscale. We simulate the CPO evolution of polycrystalline ice under combinations of two consecutive deformation events up to high strain, using the code VPFFT (visco-plastic fast Fourier transform algorithm) within ELLE. A volume of ice is first deformed under coaxial boundary conditions, which results in a CPO. The sample is then subjected to different boundary conditions (coaxial or non-coaxial) in order to observe how the deformation regime switch impacts the CPO. The model results indicate that the second flow event tends to destroy the first, inherited fabric with a range of transitional fabrics. However, the transition is slow when crystallographic axes are critically oriented with respect to the second imposed regime. Therefore, interpretations of past deformation events from observed CPOs must be carried out with caution, particularly in areas with complex deformation histories

PPAR gamma 2 Prevents Lipotoxicity by Controlling Adipose Tissue Expandability and Peripheral Lipid Metabolism

Peroxisome proliferator activated receptor gamma 2 (PPARg2) is the nutritionally regulated isoform of PPARg. Ablation of PPARg2 in the ob/ob background, PPARg2(−/−) Lep(ob)/Lep(ob) (POKO mouse), resulted in decreased fat mass, severe insulin resistance, β-cell failure, and dyslipidaemia. Our results indicate that the PPARg2 isoform plays an important role, mediating adipose tissue expansion in response to positive energy balance. Lipidomic analyses suggest that PPARg2 plays an important antilipotoxic role when induced ectopically in liver and muscle by facilitating deposition of fat as relatively harmless triacylglycerol species and thus preventing accumulation of reactive lipid species. Our data also indicate that PPARg2 may be required for the β-cell hypertrophic adaptive response to insulin resistance. In summary, the PPARg2 isoform prevents lipotoxicity by (a) promoting adipose tissue expansion, (b) increasing the lipid-buffering capacity of peripheral organs, and (c) facilitating the adaptive proliferative response of β-cells to insulin resistance

Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.This research was funded by INSTITUTO DE SALUD CARLOS III, institutional project Spain UDP and grant PT20CIII/00009.S

Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress

Towards two identification methods for breeding pigs: possibilities of a combined ear tag

The objective of this study is to develop a reliable, practical and affordable combined farm and slaughter identification for Dutch breeding pigs (sows and boars) before 1 January 2012. In consultation with representatives of pig farmers, breeding institutions, traders, slaughterhouses and governments a list of requirements for the combined ear tag has been set up. After initial interest for prototyping nine manufacturers have been visited and the requirements were discussed. Ultimately, six of the manufacturers produced a total of 13 prototypes for testing. Prototypes were subjected to a visual test and a test in two different slaughterhouses. Only four of the 13 prototypes met the established slaughterhouse criteria (loss rate <5%). These four were then tested on three pig farms. The infections, irritations and inflammation depend on husbandry conditions and the type of ear tag. The on farm loss rate of ear tag prototypes was less than 2%. The readability of the combined ear tags on the farms is not problematic. Retagging after loss was possible for one person using the existing hole but resulted in slight discomfort for the animal. During transport of the animals there were no losses. In the following slaughterhouse test no physical losses occurred. However, the functional loss rate in the slaughterhouse was above 5%. Practical implementation of the combined ear tags was studied by interviews with several stakeholders. Focus in the interviews was on the regulations, the attachment of the combined ear tags, the process of transporting pigs to the slaughterhouse, including transport, assembly and export, the need to renumber pigs, the service of the slaughterhouses for blood sampling, and the I&R in relation to the needed documentation and forms during transport. From the interviews it becomes clear that implementation in practice needs numerous reattachments and renumbering of ear tags. This leads to slight discomfort to the animals and increased labour for the farmers. This retagging has negative influence on the reliability of the data and on the guarantees of food safety. The results lead to the overall conclusion that the introduction of a combined ear tag under the current conditions is not justified as a solution to go from three to two identification procedures for breeding pigs

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Geometrical softening of a competent layer during folding

X Congreso Geológico de España, 5-7 Julio 2021, Vitoria - GasteizEl estudio de los patrones de plegamiento es utilizado en geología para obtener información sobre la reología de las rocas y cinemática de la deformación. El análisis sistemático de los parámetros mecánicos durante el plegamiento, nos proporciona una información relevante sobre el comportamiento mecánico del plegamiento. En esta contribución estudiamos la evolución del estrés y la deformación del plegamiento de rocas, a través de un método de elementos finitos (FEM), en dos dimensiones, que simula la deformación viscosa no lineal de una capa competente. Las simulaciones se realizan variando la vorticidad (cizalla pura o simple), el contraste de competencia entre la capa y la matriz (m) y el exponente de estrés (n). En las simulaciones la amplificación del plegamiento comienza cuando el segundo invariante del tensor de tasa de deformación se desvía de la curva teórica para un material homogéneo (m=1). Cuando el contraste de viscosidad es mayor, la reología es no lineal y las capas están orientadas a un alto ángulo respecto al plano de cizalla, la amplificación del plegamiento comienza antes. En condiciones de cizalla pura, el ablandamiento de la capa competente producido por la geometría del plegamiento (i.e. geometrical softening) es seguido por una fase de endurecimiento. Mientras que en cizalla simple, éste es seguido por una fase de mayor ablandamiento. Estos resultados sugieren que la causa del ablandamiento de las capas litosféricas en el límite corteza-manto puede ser debido a la tectónica sin necesidad de un cambio en las propiedades de las rocas por reacciones metamórficas o microestructurales (reducción de tamaño de grano u orientación cristalina) (Llorens, 2019).The study of fold patterns gives us information about rock rheology and kinematics of deformation. The systematic analysis of the evolution of mechanical parameters during rock folding can provide additional key information on the mechanical behaviour of rocks. In order to investigate the stress and strain evolution of rocks during fold development, a series of two-dimensional FEM simulations of non-linear single-layer folding are presented. The kinematics of deformation, the competence contrast between the folding layer and matrix (m) as well as the stress exponent of the power-law viscous material (n) are systematically varied. These parameters determine when the fold amplification starts, which in all simulations occurs when the second invariant of the strain rate tensor in the competent layer deviates from the theoretical strain rate curve for a homogeneous material (m=1). The folding process is more effective in cases with high viscosity contrast, non-linear rheology and layers oriented at a low angle with respect to the shear plane. The geometrical softening experienced by the competent layer due to fold development is followed by a hardening stage in pure shear and by a major softening in simple shear. These results suggest that the behaviour of a lithospheric layer around the crust-mantle boundary may experience geometrical softening depending on the tectonic settings rather than material softening due metamorphic reactions or microstructural changes (grain size or crystal preferred orientation) (Llorens, 2019)

Adaptation and failure of pancreatic β cells in murine models with different degrees of metabolic syndrome

The events that contribute to the expansion of β-cell mass and enhanced β-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that β-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of β cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the β cells, (2) identify molecular effectors that contribute to increasing β-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate β-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of β-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult β cells contribute to the failure of the POKO β cell. Our results indicate that the rapid development of insulin resistance and β-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and β-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in β cells with either therapeutic or diagnostic potential

Altered plasma-type gelsolin and amyloid-β in neonates with hypoxic-ischaemic encephalopathy under therapeutic hypothermia.

Hypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication responsible for ∼23% of all neonatal deaths. Also, 30-70% of these patients will suffer lifetime disabilities, including learning impairment, epilepsy or cerebral palsy. However, biomarkers for HIE screening, or monitoring disease progression are limited. Herein, we sought to evaluate the clinical usefulness of plasma-type gelsolin (pGSN) and amyloid-beta (Aβ) 40 and 42 as prognostic biomarkers for HIE. pGSN has been previously suggested as a feasible marker in other brain injuries and amyloid-beta 40 and 42 are classically assessed in neurodegenerative diseases. However, to our knowledge, they have not been previously assessed in HIE patients. We have analyzed plasma pGSN and Aβ 40 and 42 levels in 55 newborns (16 controls, 16 mild and 23 moderate-severe HIE) at birth, during 72 h of therapeutic hypothermia, a gold-standard treatment for HIE, and 24 h after hypothermia. Aβ levels were lower in HIE patients, and pGSN levels were progressively reduced in mild and moderate-severe HIE patients. The fact that pGSN reductions could predict the severity of HIE and significantly correlated with the time to undergo hypothermia supports the prognostic value of plasmatic pGSN. Further studies are warranted to investigate the role of pGSN in neonatal HIE