Effect of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Alpha Variants on Spontaneous Clearance and Fibrosis Progression during Hepatitis C Virus Infection in Moroccan Patients

Virologica Sinica - Hepatitis C virus (HCV) is still one of the main causes of liver disease worldwide. Metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), induced by HCV have...     

A single Na+-Pi cotransporter in Toxoplasma plays key roles in phosphate import and control of parasite osmoregulation

Inorganic ions such as phosphate, are essential nutrients required for a broad spectrum of cellular functions and regulation. During infection, pathogens must obtain inorganic phosphate (P_i) from the host. Despite the essentiality of phosphate for all forms of life, how the intracellular parasite Toxoplasma gondii acquires P_i from the host cell is still unknown. In this study, we demonstrated that Toxoplasma actively internalizes exogenous P_i by exploiting a gradient of Na⁺ ions to drive P_i uptake across the plasma membrane. The Na⁺-dependent phosphate transport mechanism is electrogenic and functionally coupled to a cipargarmin sensitive Na⁺-H⁺-ATPase. Toxoplasma expresses one transmembrane P_i transporter harboring PHO4 binding domains that typify the PiT Family. This transporter named TgPiT, localizes to the plasma membrane, the inward buds of the endosomal organelles termed VAC, and many cytoplasmic vesicles. Upon P_i limitation in the medium, TgPiT is more abundant at the plasma membrane. We genetically ablated the PiT gene, and ΔTgPiT parasites are impaired in importing P_i and synthesizing polyphosphates. Interestingly, ΔTgPiT parasites accumulate 4-times more acidocalcisomes, storage organelles for phosphate molecules, as compared to parental parasites. In addition, these mutants have a reduced cell volume, enlarged VAC organelles, defects in calcium storage and a slightly alkaline pH. Overall, these mutants exhibit severe growth defects and have reduced acute virulence in mice. In survival mode, ΔTgPiT parasites upregulate several genes, including those encoding enzymes that cleave or transfer phosphate groups from phosphometabolites, transporters and ions exchangers localized to VAC or acidocalcisomes. Taken together, these findings point to a critical role of TgPiT for P_i supply for Toxoplasma and also for protection against osmotic stresses.     

The emerging roles of lactate as a redox substrate and signaling molecule in adipose tissues

Journal of Physiology and Biochemistry - Thermogenic (brown and beige) adipose tissues improve glucose and lipid homeostasis and therefore represent putative targets to cure obesity and related...     

A Plasmodium homolog of ER tubule-forming proteins is required for parasite virulence

Reticulon and REEP family of proteins stabilize the high curvature of endoplasmic reticulum (ER) tubules. Plasmodium berghei Yop1 (PbYop1) is a REEP5 homolog in Plasmodium. Here, we characterize its function using a gene-knockout (Pbyop1∆). Pbyop1∆ asexual stage parasites display abnormal ER architecture and an enlarged digestive vacuole. The erythrocytic cycle of Pbyop1∆ parasites is severely attenuated and the incidence of experimental cerebral malaria is significantly decreased in Pbyop1∆-infected mice. Pbyop1∆ sporozoites have reduced speed, are slower to invade host cells but give rise to equal numbers of infected HepG2 cells, as WT sporozoites. We propose that PbYOP1’s disruption may lead to defects in trafficking and secretion of a subset of proteins required for parasite development and invasion of erythrocytes. Furthermore, the maintenance of ER morphology in different parasite stages is likely to depend on different proteins.     

lca_algebraic: a library bringing symbolic calculus to LCA for comprehensive sensitivity analysis

The International Journal of Life Cycle Assessment - In this paper, we present new tools to ease the analysis of the effect of variability and uncertainty on life cycle assessment (LCA) results....     

Developing of a model to predict lying behavior of dairy cows on silvopastoral system during the winter season

International Journal of Biometeorology - Lying behavior is an important indicator of the cows’ welfare and health. In this study, we evaluate the effect of the physical environment on dairy...     

Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair

Of the many crucial functions of the ER, homeostasis of physiological calcium increase is critical for signaling. Plasma membrane (PM) injury causes a pathological calcium influx. Here, we show that the ER helps clear this surge in cytoplasmic calcium through an ER-resident calcium pump, SERCA, and a calcium-activated ion channel, Anoctamin 5 (ANO5). SERCA imports calcium into the ER, and ANO5 supports this by maintaining electroneutrality of the ER lumen through anion import. Preventing either of these transporter activities causes cytosolic calcium overload and disrupts PM repair (PMR). ANO5 deficit in limb girdle muscular dystrophy 2L (LGMD2L) patient cells compromises their cytosolic and ER calcium homeostasis. By generating a mouse model of LGMD2L, we find that PM injury causes cytosolic calcium overload and compromises the ability of ANO5-deficient myofibers to repair. Addressing calcium overload in ANO5-deficient myofibers enables them to repair, supporting the requirement of the ER in calcium homeostasis in injured cells and facilitating PMR.     

The intrinsically disordered N-terminus of the voltage-dependent anion channel

The voltage-dependent anion channel (VDAC) is a critical β-barrel membrane protein of the mitochondrial outer membrane, which regulates the transport of ions and ATP between mitochondria and the cytoplasm. In addition, VDAC plays a central role in the control of apoptosis and is therefore of great interest in both cancer and neurodegenerative diseases. Although not fully understood, it is presumed that the gating mechanism of VDAC is governed by its N-terminal region which, in the open state of the channel, exhibits an α-helical structure positioned midway inside the pore and strongly interacting with the β-barrel wall. In the present work, we performed molecular simulations with a recently developed force field for disordered systems to shed new light on known experimental results, showing that the N-terminus of VDAC is an intrinsically disordered region (IDR). First, simulation of the N-terminal segment as a free peptide highlighted its disordered nature and the importance of using an IDR-specific force field to properly sample its conformational landscape. Secondly, accelerated dynamics simulation of a double cysteine VDAC mutant under applied voltage revealed metastable low conducting states of the channel representative of closed states observed experimentally. Related structures were characterized by partial unfolding and rearrangement of the N-terminal tail, that led to steric hindrance of the pore. Our results indicate that the disordered properties of the N-terminus are crucial to properly account for the gating mechanism of VDAC.