SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells.     

Beneficial and Sexually Dimorphic Response to Combined HDAC Inhibitor Valproate and AMPK/SIRT1 Pathway Activator Resveratrol in the Treatment of ALS Mice

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice’s survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice.     

CD26 Induces Colorectal Cancer Angiogenesis and Metastasis through CAV1/MMP1 Signaling

CD26 has been reported as a marker for colorectal cancer stem cells endowed with tumor-initiating properties and capable of colorectal cancer (CRC) metastasis. In this study, we investigated the functional effect of CD26 on CRC angiogenesis and metastasis, and the potential underlying mechanism. The functional effects of CD26 overexpression or repression were determined by a wound healing experiment, and cell migration and invasion assays in vitro and in mouse models. Differentially expressed genes regulated by CD26 were identified by genome-wide mRNA expression array and validated by quantitative PCR. CD26 functionally regulated CRC cell migration and invasion in vitro and angiogenesis and metastasis in vivo. Genome-wide mRNA expression array and qPCR showed that MMP1 was up-regulated in CD26+ subpopulation, and a subsequent experiment demonstrated the regulatory effect of CD26 on MMP1 in CRC cell lines with CD26 repression or overexpression. Furthermore, overexpression of CAV1 abrogated the CD26-regulated MMP1 induction in CRC cell lines. This study demonstrated the functional roles of CD26 in inducing CRC migration, invasion, angiogenesis and metastasis and identified the potential involvement of MMP1 and CAV1 in such process. CD26 is an attractive therapeutic target for combating tumor progression to improve the prognosis of CRC patients.     

Effects of Sedentarism and Treadmill Training in Mechanical Properties of Muscles of Ovariectomized Rats with High-Fat Diet

The aim of this study is to evaluate the ability of physical training in the maintenance of muscle strength in rats with HFD （high-fat diet） after OVX （ovariectomy）. Eighty Wistar rats are at eight weeks of age and weight 200 g which divided into 8 groups （n = 10） and treated for 12 weeks： GA： OVX ＋ ND （normal diet）, GB： OVX ＋ ND ＋ training, GC： sham ＋ ND, GD： sham ＋ ND ＋ training, GE： OVX ＋ HFD, GF： OVX ＋ HFD ＋ training, GG： sham ＋ HFD and GH： sham ＋ HFD ＋ training. HFD consists of standard ration for rats with addition of 30% lipids. In training groups, physical training five training/week was conducted on a treadmill with adaptation period of three weeks up to 18 m/s for one hour, training were performed for 12 weeks. The sedentary animals remained in individual box. To analyze the effects of training and diet, tensile strength tests of the gastrocnemius muscles were conducted： the speed of 0.1 mm/min. Analysis of variance was performed to compare groups. The mean （SD） obtained for the maximum load （N） were： GA 57.77 （6.89）, GB 62.74 （5.07）, GC 49.45 （6.06）, GD 59.42 （5.26） and GE 55.58 （4.72）, GF 62.50 （4.56）, GG 58.35 （4.54） and GH 56.67 （5.87）, respectively. There were no differences for maximum load between surgeries （p = 0.004） and between treatments （p = 0.000）. Differences were found also for the relationship surgery diet treatment （p = 0.007）. For the variable stiffness （N/mm）, there were not statistically significant differences： GA 5.03 （0.72）, GB 5.08 （1.09）, GC 5.17 （0.53）, GD 5.35 （0.80）, GE 5.52 （1.20）, GF 5.36 （1.07）, GG 4.83 （1.03） and GH 5.40 （0.73）. For the toughness （N/mm）, there were differences between treatments （p = 0.010） and the ratio diet treatment （p = 0.024）： GA 455.00 （107.21）, GB 541.96 （126.80）, GC 394.97 （84.67）, GD 566.90 （157.07）; GE 424.63 （113.03）, GF 478.07 （106.03）; GG 517.44 （98.65?     

Nutrient balance of shifting cultivation by burning or mulching in the Eastern Amazon – evidence for subsoil nutrient accumulation

For over a hundred years shifting cultivation with slash-and-burn land preparation has been the predominant type of land use by smallholders in the Bragantina region of the Brazilian Eastern Amazon. This study contrasts the nutrient balance of slash-and-burn agriculture with a fire-free cultivation. Therefore, one half of a 3.5-year-old (28.7 t DM ha^–1) and a 7-year-old woody fallow vegetation (46.5 t DM ha^–1) was burnt and the other half mulched, leaving the biomass as a surface residue. Subsequently, a sequence of maize, beans and cassava was cropped for 1.5 year. Burning the 3.5- and 7-year-old fallow removed 97 and 94% of the C, 98 and 96% of the N, 90 and 63% of the P-stocks, and between 45 and 70% of the cations K, Mg and Ca of the aboveground biomass by volatilization or ash-particle transfer. These losses were avoided with the slash-and-mulch land preparation. Mulching did not increase the losses of nutrients by leaching, despite the high amount of rapidly decomposing surface mulch. Also the length of preceding fallow had no significant influence on leaching losses. At a depth of 3 m, leached nutrients were quantitatively negligible in both treatments. Comparing the nutrient fluxes at soil depths of 0.9 m, 1.8 m and 3 m, the amounts of all mobile nutrients, and also of chloride and sodium were markedly reduced during percolation and must have been retained. It is likely that nutrient retention in the subsoil layer is only temporary, emphasizing the need for a rapid re-establishment of the naturally deep-rooting secondary vegetation after abandonment of sites to enable uptake of these nutrients. The overall nutrient balance was highly negative for slash-and-burn. 291 and 403 kg N ha^–1, 21 and 18 kg P ha^–1, and 70 and 132 kg K ha^–1 were removed from the burnt plots with a preceding fallow of 3.5 and 7 years, respectively. A reduced fallow period (3.5 years), which is a common trend in the region, resulted in a higher mean annual rate of nutrient loss averaged over the duration of the cycle than a fallow period of 7 years. Eliminating the burning losses by mulching brought the agricultural system back to an equilibrated or even slightly positive nutrient balance, even after a reduced fallow period. Thus, slash-and-mulch is a viable alternative to maintain agricultural productivity and ecosystem functioning.     

Pd/Ce0.6Zr0.4O2/Al2O3 as advanced materials for three-way catalysts: Part 1. Catalyst characterisation, thermal stability and catalytic activity in the reduction of NO by CO

Pd-loaded Ce_0.6Zr_0.4O₂ solid solutions supported on Al₂O₃ are investigated as catalysts for the reduction of NO by CO. The attention is focused on the role of the Ce_0.6Zr_0.4O₂ and of the Pd dispersion on the catalytic activity. The system shows a very high activity below 500 K, which is almost independent on the Pd dispersion. The high activity is attributed to a promoting effect of the Ce_0.6Zr_0.4O₂ on the NO conversion. Investigation of the influence of high temperature treatments disclosed a thermal stabilisation of both Ce_0.6Zr_0.4O₂ and Al₂O₃ in the Ce_0.6Zr_0.4O₂/Al₂O₃ system.     

L'Épaisseur d'un décimètre carré 1

Résumé:

Le présent article illustre les difficultés qui peuvent surgir lorsque la distinction entre les notions mathématiques et leurs modèles issus du monde physique n'est pas bien comprise. Les exemples fournis touchent divers ordres d'enseignement, notamment celui de la formation des enseignantes et des enseignants pour le primaire.