Targeting mitochondrial 18 kDa translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype

Abstract The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically and by the use of selective TSPO ligands

Designing sequential transcription logic: a simple genetic circuit for conditional memory

The ability to learn and respond to recurrent events depends on the capacity to remember transient biological signals received in the past. Moreover, it may be desirable to remember or ignore these transient signals conditioned upon other signals that are active at specific points in time or in unique environments. Here, we propose a simple genetic circuit in bacteria that is capable of conditionally memorizing a signal in the form of a transcription factor concentration. The circuit behaves similarly to a "data latch" in an electronic circuit, i.e. it reads and stores an input signal only when conditioned to do so by a "read command". Our circuit is of the same size as the well-known genetic toggle switch (an unconditional latch) which consists of two mutually repressing genes, but is complemented with a "regulatory front end" involving protein heterodimerization as a simple way to implement conditional control. Deterministic and stochastic analysis of the circuit dynamics indicate that an experimental implementation is feasible based on well-characterized genes and proteins. It is not known, to which extent molecular networks are able to conditionally store information in natural contexts for bacteria. However, our results suggest that such sequential logic elements may be readily implemented by cells through the combination of existing protein-protein interactions and simple transcriptional regulation.Comment: 20 pages, 5 figures; supplementary material available upon request from the author

Renal function in patients with anemia and severe chronic heart failure: effects of iron medications

Aim. To investigate the prevalence of anemia and renal dysfunction combination among patients with severe chronic heart failure (CHF), as well as the effects of intravenous (i/v) iron therapy.Material and methods. In total, 42 patients (mean age 69,3+1,2 years) with Functional Class III-IV stable CHF (NYHA classification) were examined. Glomerular filtration rate (GFR) was calculated based on creatinine concentration (MDRD formula). Anemia was diagnosed by WHO criteria: hemoglobin (Hb) level <130 g/1 in men and <120 g/1 in women. Eleven patients were administered Venofer for 24 weeks. At baseline and after the treatment course, 6-minute walk test (6mw) was performed.Results. Anemia was diagnosed in 17 (40,5%) patients, including 13 with iron deficiency. Chronic renal failure (CRF; GFR< 60 ml/min) was observed in 64,7 % of the participants. Clinical and laboratory parameters were compared in patients with cardiorenal syndrome (GFR<60 ml/min) with or without anemia. Significant negative correlation was observed between Hb and creatinine levels (p=-0,02), with positive correlation between hematocrit (Ht) and GFR levels (p=0,044). Intravenous iron therapy was associated with a significant increase in Hb (from 128,2+14,4 to 139,0+17,4 g/1; p=0,03), Ht (from 38,4+3,5 to 41,3+5,06; p=0,03), and physical stress tolerance (PST), according to 6mw test results.Conclusion. The combination of cardiac pathology, renal dysfunction and iron-deficient anemia was typical of patients with severe CHF. Iron therapy was associated with significant increase in Hb, Ht, and PST levels, without any severe adverse effects

A C-Terminal Region of Yersinia pestis YscD Binds the Outer Membrane Secretin YscC▿†

YscD is an essential component of the plasmid pCD1-encoded type III secretion system (T3SS) of Yersinia pestis. YscD has a single transmembrane (TM) domain that connects a small N-terminal cytoplasmic region (residues 1 to 121) to a larger periplasmic region (residues 143 to 419). Deletion analyses established that both the N-terminal cytoplasmic region and the C-terminal periplasmic region are required for YscD function. Smaller targeted deletions demonstrated that a predicted cytoplasmic forkhead-associated (FHA) domain is also required to assemble a functional T3SS; in contrast, a predicted periplasmic phospholipid binding (BON) domain and a putative periplasmic “ring-building motif” domain of YscD could be deleted with no significant effect on the T3S process. Although deletion of the putative “ring-building motif” domain did not disrupt T3S activity per se, the calcium-dependent regulation of the T3S apparatus was affected. The extreme C-terminal region of YscD (residues 354 to 419) was essential for secretion activity and had a strong dominant-negative effect on the T3S process when exported to the periplasm of the wild-type parent strain. Coimmunoprecipitation studies demonstrated that this region of YscD mediates the interaction of YscD with the outer membrane YscC secretin complex. Finally, replacement of the YscD TM domain with a TM domain of dissimilar sequence had no effect on the T3S process, indicating that the TM domain has no sequence-specific function in the assembly or function of the T3SS

The Vesicle-inducing Protein 1 from Synechocystis sp. PCC 6803 Organizes into Diverse Higher-Ordered Ring Structures

The vesicle-inducing protein in plastids 1 (Vipp1) was found to be involved in thylakoid membrane formation in chloroplasts and cyanobacteria. In contrast to chloroplasts, it has been suggested that in cyanobacteria the protein is only tightly associated with the cytoplasmic membrane. In the present study we analyze and describe the subcellular localization and the oligomeric organization of Vipp1 from the cyanobacterium Synechocystis PCC 6803. Vipp1 forms stable dimers and higher-ordered oligomers in the cytoplasm as well as at both the cytoplasmic and thylakoid membrane. Vipp1 oligomers are organized in ring structures with a variable diameter of 25–33 nm and corresponding calculated molecular masses of ∼1.6–2.2 MDa. Six different types of rings were found with an unusual 12–17-fold symmetrical conformation. The simultaneous existence of multiple types of rings is very unusual and suggests a special function of Vipp1. Involvement of diverse ring structures in vesicle formation is suggested