Altered mRNA and Protein Expression of Monocarboxylate Transporter MCT1 in the Cerebral Cortex and Cerebellum of Prion Protein Knockout Mice

The effect of a cellular prion protein (PrP^c) deficiency on neuroenergetics was primarily analyzed via surveying the expression of genes specifically involved in lactate/pyruvate metabolism, such as monocarboxylate transporters (MCT1, MCT2, MCT4). The aim of the present study was to elucidate a potential involvement of PrP^c in the regulation of energy metabolism in different brain regions. By using quantitative real-time polymerase chain reaction (qRT-PCR), we observed a marked reduction in MCT1 mRNA expression in the cortex of symptomatic Zürich I Prnp^−/− mice, as compared to their wild-type (WT) counterparts. MCT1 downregulation in the cortex was accompanied with significantly decreased expression of the MCT1 functional interplayer, the Na⁺/K⁺ ATPase α2 subunit. Conversely, the MCT1 mRNA level was significantly raised in the cerebellum of Prnp^−/− vs. WT control group, without a substantial change in the Na⁺/K⁺ ATPase α2 subunit expression. To validate the observed mRNA findings, we confirmed the observed change in MCT1 mRNA expression level in the cortex at the protein level. MCT4, highly expressed in tissues that rely on glycolysis as an energy source, exhibited a significant reduction in the hippocampus of Prnp^−/− vs. WT mice. The present study demonstrates that a lack of PrP^c leads to altered MCT1 and MCT4 mRNA/protein expression in different brain regions of Prnp^−/− vs. WT mice. Our findings provide evidence that PrP^c might affect the monocarboxylate intercellular transport, which needs to be confirmed in further studies.     

The Multifunctional Sactipeptide Ruminococcin C1 Displays Potent Antibacterial Activity In Vivo as Well as Other Beneficial Properties for Human Health

The world is on the verge of a major antibiotic crisis as the emergence of resistant bacteria is increasing, and very few novel molecules have been discovered since the 1960s. In this context, scientists have been exploring alternatives to conventional antibiotics, such as ribosomally synthesized and post-translationally modified peptides (RiPPs). Interestingly, the highly potent in vitro antibacterial activity and safety of ruminococcin C1, a recently discovered RiPP belonging to the sactipeptide subclass, has been demonstrated. The present results show that ruminococcin C1 is efficient at curing infection and at protecting challenged mice from Clostridium perfringens with a lower dose than the conventional antibiotic vancomycin. Moreover, antimicrobial peptide (AMP) is also effective against this pathogen in the complex microbial community of the gut environment, with a selective impact on a few bacterial genera, while maintaining a global homeostasis of the microbiome. In addition, ruminococcin C1 exhibits other biological activities that could be beneficial for human health, as well as other fields of applications. Overall, this study, by using an in vivo infection approach, confirms the antimicrobial clinical potential and highlights the multiple functional properties of ruminococcin C1, thus extending its therapeutic interest.     

Intensification of vibration mixing of particulate solids by means of multi-layer loading of components

The objective of the study is to show how initial distribution of dissimilar particulate components influences the mixing time and mixture quality. The dissimilar components have a tendency to segregate in one another, and it is impossible to achieve the perfect mixture of them in industrial settings. Nevertheless, the situation can be improved if the components are loaded as a sequence of several sandwiches, each of these sandwiches containing layers of components that are proportional to their share in the mixture. In this case, a sort of pre-mixing occurs while still at the loading stage – which allows reducing the optimum mixing time and increasing the homogeneity of the mixture. The theory of Markov chains was used to simulate the mixing kinetics. It is shown that the number of loaded sandwiches has a very strong influence on the process efficiency. A loading device that can effectively realize multi-layer loading is proposed. The mixing kinetics for ternary mixture of glass beads was investigated experimentally at a lab scale vibration mixer. A one-time loading and a two-sandwich loading were compared. It was shown that the optimum mixing time and non-homogeneity of the mixture were reduced by half in the latter case.     

Phthalate removal throughout wastewater treatment plant: Case study of Marne Aval station (France)

The fate of six phthalates: dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DnBP), butyl benzyl phthalate (BBP), bis (2-ethylhexyl) phthalate (DEHP) and di-n-octyl phthalate (DnOP) was investigated throughout wastewater treatment processes in the wastewater treatment plant (WWTP) of Marne Aval (France). That plant treats wastewater from a highly populated area and was used as a pilot station for development of nitrification processes.In wastewater, at each step of treatment, DEHP was always the major compound (9 to 44 µg L^− 1), followed by DEP (1.6 to 25 µg L^− 1). Other phthalates averaged 1 µg L^− 1 and DnOP remained close to the detection limit in nearly all cases.In sludge, the prevailing compound was also DEHP (72 µg g^− 1) which is consistent with its tendency to get sorbed upon suspended matter (SM). DnOP came in third, in relation with its resistance to biodegradation.For the studied period, the removal efficiency of DEHP from wastewater was about 78%. That removal seemed to proceed rather from particle settling than from biodegradation. A highly significant correlation (p < 0.001) was found between DEHP and SM concentrations throughout treatment processes. The other compounds: DMP, DEP, DnBP and BBP, displayed satisfactory efficiencies ranging from 68 to over 96% for the lighter ones obviously more easily degraded.Under rainy periods, the plant discharge impact upon Marne River quality in terms of phthalate fluxes, appeared to be minor as compared to the amount brought by the storm overflows in the same area. Downstream of the WWTP discharge, DEHP concentration remained under the European norm for surface water (NQE: 1.3 µg L^− 1).Our study documents the behaviour of phthalate esters throughout a WWTP which treatment device is used by 55% of the WWTP in the river Seine basin.     

Continuous mixing of powder mixtures with pharmaceutical process constraints

While it would provide many advantages from many aspects, the application of continuous mixing processes to the pharmaceutical field is still in its infancy. In this paper we report results concerning the continuous mixing of nine ingredients (including three actives) that constitute a current drug. We examine these results in the light of different pharmaceutical process constraints, such as mixture quality control, time-stability of this quality, sensitivity of the process to perturbations. The apparatus is a pilot plant Gericke GCM 500 continuous mixer with three loss-in-weight feeders. A specific experimental protocol is developed to determine the homogeneity of the mixtures at the outlet of the mixer. The homogeneity of the mixtures is examined through industrial standards that would allow the product to be released on the market. The steady-state operation is first reported on, and it is demonstrated that a very acceptable mixture can be produced under certain conditions, with excellent time stability. The response of the mixer to filling sequences of two critical feeders is also quantified in terms of mixture homogeneity. It is found that it may be preferable to stop the process during these periods.     

Human IPSC-Derived Model to Study Myelin Disruption

Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also assessed by Western blot. We identified compounds capable of inducing developmental neurotoxicity by disrupting myelin in a systematic review to evaluate the relevance of our BrainSphere model for the study of the myelination/demyelination processes. Results demonstrated that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested (Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, but not methyl mercury) decreased myelination, while ibuprofen (negative control) had no effect. Here, we define a methodology that allows quantification of myelin disruption and provides reference compounds for chemical-induced myelin disruption.     

The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

The endothelium plays a key role in blood vessel health. At the interface of the blood, it releases several mediators that regulate local processes that protect against the development of cardiovascular disease. In this interplay, there is increasing evidence for a role of extracellular nucleotides and endothelial purinergic P2Y receptors (P2Y-R) in vascular protection. Recent advances have revealed that endothelial P2Y₁-R and P2Y₂-R mediate nitric oxide-dependent vasorelaxation as well as endothelial cell proliferation and migration, which are processes involved in the regeneration of damaged endothelium. However, endothelial P2Y₂-R, and possibly P2Y₁-R, have also been reported to promote vascular inflammation and atheroma development in mouse models, with endothelial P2Y₂-R also being described as promoting vascular remodeling and neointimal hyperplasia. Interestingly, at the interface with lipid metabolism, P2Y₁₂-R has been found to trigger HDL transcytosis through endothelial cells, a process known to be protective against lipid deposition in the vascular wall. Better characterization of the role of purinergic P2Y-R and downstream signaling pathways in determination of the endothelial cell phenotype in healthy and pathological environments has clinical potential for the prevention and treatment of cardiovascular diseases.