Selective HDAC6 Inhibition Corrects Aberrant B Cell Development in the Bone Marrow of NZB/W F1 Mice

B cell development in the bone marrow is highly complex and includes vital regulatory checkpoints to maintain central tolerance. Defects in central tolerance are implicated in systemic lupus erythematosus (SLE) and aberrant B cell development has been reported in NZB/W mice.

We hypothesized that altered B cell development in the bone marrow of lupus-prone NZB/W mice would be corrected after HDAC6 inhibition. B cell development was evaluated by flow cytometric analysis of Hardy fractions from bone marrow cells of NZB/W mice treated with an HDAC6 inhibitor or vehicle control.

Additionally, deep sequence analysis of RNA from the bone marrow was utilized to identify potential targets of HDAC6. As NZB/W mice aged, there was an apparent shift in later stages of B cell development suggesting accelerated progression through maturation and potential to bypass key regulatory checkpoints.

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Endotoxin and Other Microbial Translocation Markers in the Blood: A Clue to Understand Leaky Gut Syndrome

Gut affects various systems in the human body. The leaky gut hypothesis tells us that gut microbial products cause systemic low-grade inflammation, which enhances the progression of various human diseases.

Microbial translocation attributable to intestinal barrier dysfunction and hyperpermeability have been proven in major human diseases. Among these microbial products, endotoxin/ lipopolysaccharide is most extensively studied in clinical situations.

However, its detection in the blood and its impact in the clinical course still arouse much discussion. Overviewing the long-standing controversies in the assay system and the main results in various clinical situations, this review regards plasma endotoxin level as a feasible microbial translocation marker.

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Endotoxin and Other Microbial Translocation Markers in the Blood: A Clue to Understand Leaky Gut Syndrome

Gut affects various systems in the human body. The leaky gut hypothesis tells us that gut microbial products cause systemic low-grade inflammation, which enhances the progression of various human diseases.

Microbial translocation attributable to intestinal barrier dysfunction and hyperpermeability have been proven in major human diseases. Among these microbial products, endotoxin/ lipopolysaccharide is most extensively studied in clinical situations.

However, its detection in the blood and its impact in the clinical course still arouse much discussion. Overviewing the long-standing controversies in the assay system and the main results in various clinical situations, this review regards plasma endotoxin level as a feasible microbial translocation marker.

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Three-Dimensional Architecture of the L-Type Calcium Channel: Structural Insights into the CaVα2δ1 Auxiliary Protein

L-type calcium channels (LTCC) are responsible for Ca2+ influx into muscle and neurons. These macromolecular complexes minimally comprise the main poreforming CaVα1 and auxiliary subunits CaVβ and CaVα2δ1.

The ultrastructure of the oligomeric LTCC complexes from heart and skeletal muscle has been reported previously at ≈ 20 Å, a resolution that prevent identification of structural domains.

Recent improvements in cryo-electronic microscopy (EM) methods made it possible to obtain a three-dimensional structure of the rabbit skeletal muscle LTCC CaV1.1 complex at a resolution of 4.2 Å and recently at 3.6 Å. This technique requires only nanograms of purified proteins and circumvents crystallization as a means for structure determination.

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Identification of Key Functional Residues in the Active Site of Vitamin K Epoxide Reductase-like Protein

The vitamin K epoxide reductase (VKOR) activity has been described since the early 70s’. This VKOR activity allows the reduction of vitamin K epoxide in order to regenerate vitamin K quinone. This activity is a key step of the vitamin cycle and is the target of vitamin K antagonist (VKA).

The VKORC1 gene has only been identified in 2004. This gene encodes for a 163 amino acid protein with, probably, four transmembrane domains and a luminal loop. This protein contains also a C132XXC135 redox motif, as previously hypothesized by Silverman. This motif is located in the fourth transmembrane domain.

VKA actively inhibit VKORC1 in the liver and thus limit the gamma-carboxylation of hepatic VKD proteins resulting in an intense anticoagulant effect. VKA are extensively used worldwide for prevention and treatment of thromboembolic disorders. Many missenses mutations have been detected in VKORC1 gene in humans and rats and are sometimes associated to a VKA resistance phenotype

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Nucleosomal Barrier to Transcription | Structural Determinants and Changes in Chromatin Structure

Packaging of DNA into chromatin affects all processes on DNA. Nucleosomes present a strong barrier to transcription, raising important questions about the nature and the mechanisms of overcoming the barrier.

Recently it was shown that DNA sequence, DNA–histone interactions and backtracking by RNA polymerase II (Pol II) all contribute to formation of the barrier. After partial uncoiling of nucleosomal DNA from histone octamer by Pol II and backtracking of the enzyme, nucleosomal DNA recoils on the octamer, locking Pol II in the arrested state.

Histone chaperones and transcription factors TFIIS, TFIIF and FACT facilitate transcription through chromatin using different molecular mechanisms.

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